Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders

ABSTRACT

Devices, systems and methods are disclosed for treating or preventing gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders. The methods comprise transmitting impulses of energy non-invasively to selected nerve fibers, particularly those in a vagus nerve. The methods provide damaged interstitial cells of Cajal (ICC) with trophic factors via vagal afferent nerve fibers, thereby reversing ICC damage, and as a consequence improving gastric motility. The methods also increase levels of inhibitory neurotransmitters in the brain so as to decrease neural activity within the area postrema, or they deactivate a resting state neural network containing parts of the anterior insula and anterior cingulate cortex, which will thereby reduce abnormal interoception and visceral hypersensitivity.

CROSS REFERENCE TO RELATED APPLICATIONS Cross Reference to RelatedApplications

This application is a continuation-in-part of U.S. patent applicationSer. No. 13/603,781 filed Sep. 5, 2012, which is a continuation-in-partof U.S. patent application Ser. No. 13/222,087 filed Aug. 31, 2011,which is a continuation-in-part of U.S. patent application Ser. No.13/183,765 filed Jul. 15, 2011 which claims the benefit of priority ofU.S. Provisional Patent Application No. 61/488,208 filed May 20, 2011and is a continuation-in-part to U.S. patent application Ser. No.13/183,721 filed Jul. 15, 2011, which claims the benefit of priority ofU.S. Provisional Patent Application No. 61/487,439 filed May 18, 2011and is a continuation-in-part of U.S. patent application Ser. No.13/109,250 filed May 17, 2011, which claims the benefit of priority ofU.S. Provisional Patent Application No. 61/471,405 filed Apr. 4, 2011and is a continuation-in-part of U.S. patent application Ser. No.13/075,746 filed Mar. 30, 2011, which claims the benefit of priority ofU.S. provisional patent application 61/451,259 filed Mar. 10, 2011 andis a continuation-in-part of U.S. patent application Ser. No. 13/005,005filed Jan. 12, 2011, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/964,050 filed Dec. 9, 2010, which claims thebenefit of priority of U.S. Provisional Patent Application No.61/415,469 filed Nov. 19, 2010 and is a continuation-in-part of U.S.patent application Ser. No. 12/859,568 filed Aug. 9, 2010, which is acontinuation-in-part of U.S. patent application Ser. No. 12/408,131filed Mar. 20, 2009 and a continuation-in-part application of U.S.patent application Ser. No. 12/612,177 filed Nov. 9, 2009, now U.S. Pat.No. 8,041,428 issued Oct. 18, 2011, the entire disclosures of which arehereby incorporated by reference.

This application is also related to commonly assigned co-pending U.S.patent application Ser. No. 13/357,010 filed Jan. 24, 2012, U.S. patentapplication Ser. No. 13/357,025 filed Jan. 24, 2012, U.S. patentapplication Ser. No. 13/655,716 filed Jan. 24, 2012, U.S. ProvisionalPatent Application No. 61/585,668 filed Jan. 12, 2012 and U.S. patentapplication Ser. No. 13/671,859 filed Nov. 8, 2012 the completedisclosures of which are incorporated herein by reference for allpurposes.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with gastroparesis, functional dyspepsia, andfunctional gastrointestinal disorders generally. The energy impulses(and/or fields) that are used to treat those conditions compriseelectrical and/or electromagnetic energy, delivered non-invasively tothe patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes has been approved for use in the treatment ofvarious conditions, including pain and movement disorders such asessential tremor and Parkinson's disease.

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92 (2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST, et al].

The form of electrical stimulation that is most relevant to the presentinvention is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al; U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29 (2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann.N.Y. Acad. Sci. 993 (2003):1-13; LABINER, D. M., Ahern, G. L. Vagusnerve stimulation therapy in depression and epilepsy: therapeuticparameter settings. Acta. Neurol. Scand. 115 (2007):23-33].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the medical procedures that are disclosed herein do notinvolve surgery. Instead, the present devices and methods stimulatenerves by transmitting energy to nerves and tissue non-invasively. Amedical procedure is defined as being non-invasive when no break in theskin (or other surface of the body, such as a wound bed) is createdthrough use of the method, and when there is no contact with an internalbody cavity beyond a body orifice (e.g, beyond the mouth or beyond theexternal auditory meatus of the ear). Such non-invasive procedures aredistinguished from invasive procedures (including minimally invasiveprocedures) in that the invasive procedures insert a substance or deviceinto or through the skin (or other surface of the body, such as a woundbed) or into an internal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body. An electric field is inducedat a distance causing electric current to flow within electricallyconducting bodily tissue. The electrical circuits for magneticstimulators are generally complex and expensive and use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil to produce a magneticpulse. The principles of electrical nerve stimulation using a magneticstimulator, along with descriptions of medical applications of magneticstimulation, are reviewed in: Chris HOVEY and Reza Jalinous, The Guideto Magnetic Stimulation, The Magstim Company Ltd, Spring Gardens,Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006. In contrast,the magnetic stimulators that are disclosed herein are relativelysimpler devices that use considerably smaller currents within thestimulator coils. Accordingly, they are intended to satisfy the need forsimple-to-use and less expensive non-invasive magnetic stimulationdevices, for use in treating gastroparesis or functional dyspepsia, aswell as use in treating other conditions.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In the present invention, noninvasive electrical and/or magneticstimulation of a vagus nerve is used to treat functionalgastrointestinal disorders, which are defined as follows. Patientsfrequently consult a physician after experiencing gastrointestinal (GI)symptoms such as pain, nausea, vomiting, bloating, diarrhea,constipation, or difficult passage of food or feces. Tests are thenperformed in an effort to find an organic or structural explanation forthe symptoms, such as an infection, tumor, structural blockage,metabolic abnormality or inflammation. When the tests do not reveal anysuch organic etiology or structural lesion, the patient is diagnosed ashaving a functional gastrointestinal disorder (FGID), which is to say, aGI disorder in which there is “no known structural (i.e, no pathologicalor radiological) abnormalities, or infectious, or metabolic causes”.Examples of FGIDs are irritable bowel syndrome, functional dyspepsia andchronic constipation.

Until about thirty years ago, functional gastrointestinal disorders wereconsidered undiagnosed, uninvestigated, idiopathic or cryptogenic, orthey were simply correlated with lifestyle or psychological influencessuch as excessive psychosocial stress, because no organic causes fortheir symptoms could be identified. In this regard, FGIDs share theabsence of a straightforward, well-defined pathophysiological cause withother non-GI disorders, such as chronic fatigue syndrome, fibromyalgia,and chronic regional pain disorder [LEVY R L, Olden K W, Naliboff B D,Bradley L A, Francisconi C, Drossman D A, Creed F. Psychosocial aspectsof the functional gastrointestinal disorders. Gastroenterology 130(5,2006):1447-1458; KIM S E, Chang L. Overlap between functional GIdisorders and other functional syndromes: what are the underlyingmechanisms? Neurogastroenterol Motil 24(10, 2012):895-913; Clive HWILDER-SMITH. The balancing act: endogenous modulation of pain infunctional gastrointestinal disorders. Gut 60 (2011)1589-1599].

However, more recently, it is appreciated that a FGID is the clinicalproduct of an interaction of psychosocial factors with an altered gutphysiology that involves complex feedback between the gut and thecentral nervous system (the gut-brain axis). For example, some patientsmay experience a transient minor infection or inflammation in their GItract that would not produce symptoms in a normal individual, butbecause the digestive and nervous systems of the FGID patient havebecome hypersensitive, the FGID patient does in fact develop GI symptoms[Douglas A. DROSSMAN. The functional gastrointestinal disorders and theRome III process. Gastroenterology 130 (2006):1377-1390; WOOD J D,Alpers D H, Andrews P L. Fundamentals of neurogastroenterology. Gut 45(Supp) 2, 1999):II6-II16; GRUNDY D, Al-Chaer E D, Aziz Q, Collins S M,Ke M, Taché Y, Wood J D. Fundamentals of neurogastroenterology: basicscience. Gastroenterology 130(5, 2006):1391-1411; GEBHART G F.Pathobiology of visceral pain: molecular mechanisms and therapeuticimplications IV. Visceral afferent contributions to the pathobiology ofvisceral pain. Am J Physiol Gastrointest Liver Physiol 278(6,2000):G834-838; CRAIG A D. How do you feel? Interoception: the sense ofthe physiological condition of the body. Nat Rev Neurosci 3(8,2002):655-666; BIELEFELDT K, Christianson J A, Davis B M. Basic andclinical aspects of visceral sensation: transmission in the CNS.Neurogastroenterol Motil 17(4, 2005):488-499; MAYER E A, Naliboff B D,Craig A D. Neuroimaging of the brain-gut axis: from basic understandingto treatment of functional GI disorders. Gastroenterology 131(6,2006):1925-42; ANAND P, Aziz Q, Willert R, van Oudenhove L. Peripheraland central mechanisms of visceral sensitization in man.Neurogastroenterol Motil 19(1 Suppl, 2007):29-46; MAYER E A. Theneurobiology of stress and gastrointestinal disease. Gut 47(6,2000):861-869; MAYER E A, Collins S M. Evolving pathophysiologic modelsof functional gastrointestinal disorders. Gastroenterology 122(7,2002):2032-2048; MAYER E A, Tillisch K, Bradesi S. Review article:modulation of the brain-gut axis as a therapeutic approach ingastrointestinal disease. Aliment Pharmacol Ther 24(6, 2006):919-933;HOLZER P, Schicho R, Holzer-Petsche U, Lippe I T. The gut as aneurological organ. Wien Klin Wochenschr 113(17-18, 2001):647-60; MULAKA, Bonaz B. Irritable bowel syndrome: a model of the brain-gutinteractions. Med Sci Monit 10(4, 2004):RA55-RA62; JONES M P, Dilley JB, Drossman D, Crowell M D. Brain-gut connections in functional GIdisorders: anatomic and physiologic relationships. NeurogastroenterolMotil 18(2, 2006):91-103; MOSHIREE B, Zhou Q, Price D D, Verne G N.Central sensitisation in visceral pain disorders. Gut 55(7,2006):905-908; ZHOU Q, Verne G N. New insights into visceralhypersensitivity—clinical implications in IBS. Nat Rev GastroenterolHepato 8(6, 2011):349-355].

The present invention is concerned primarily with a stomach-related typeof FGID—functional dyspepsia, which has four specific symptoms that arethought to originate from the gastroduodenal region (viz., postprandialfullness, early satiation, epi-gastric pain, and epigastric burning).The invention is also concerned with a condition that is common amongfunctional dyspepsia patients, in which there is delayed emptying of thestomach into the intestine. The medical term for such delayed stomachemptying in the absence of structural blockage is gastropareis (partialparalysis of the stomach), which is often accompanied by chronic orintermittent nausea, vomiting, early satiety, abdominal distention aftereating, and/or abdominal pain typically following meals [MIWA H. Whydyspepsia can occur without organic disease: pathogenesis and managementof functional dyspepsia. J Gastroenterol 47(8, 2012):862-871; TACK J,Lee K J. Pathophysiology and treatment of functional dyspepsia. J ClinGastroenterol 39(5 Suppl 3, 2005):S211-6; TACK J, Masaoka T, Janssen P.Functional dyspepsia. Curr Opin Gastroenterol 27(6, 2011):549-557; TACKJ, Talley N J, Camilleri M, Holtmann G, Hu P, Malagelada J R,Stanghellini V. Functional gastroduodenal disorders. Gastroenterology130(5, 2006):1466-1479; Rita BRUN and Braden Kuo. Functional dyspepsia.Therap Adv Gastroenterol 3(3, 2010): 145-164; AGREUS L. Natural historyof dyspepsia. Gut 50 (Suppl 4, 2002):iv2-9; GEERAERTS B, Tack J.Functional dyspepsia: past, present, and future. J Gastroenterol 43(4,2008): 251-255; LOYD R A, McClellan D A. Update on the evaluation andmanagement of functional dyspepsia. Am Fam Physician 83(5,2011):547-552; HASLER W L. Gastroparesis: symptoms, evaluation, andtreatment. Gastroenterol Clin North Am 36(3, 2007):619-647; Olga HILAS.Management of Gastroparesis. US Pharm 36(12, 2011):HS15-HS18; MASAOKA T,Tack J. Gastroparesis: current concepts and management. Gut Liver 3(3,2009):166-73; PATRICK A, Epstein O. Review article: gastroparesis.Aliment Pharmacol Ther. 2008 May; 27(9, 2008):724-740; WASEEM S,Moshiree B, Draganov P V. Gastroparesis: current diagnostic challengesand management considerations. World J Gastroenterol 15(1, 2009):25-37;VITTAL H, Farrugia G, Gomez G, Pasricha P J. Mechanisms of disease: thepathological basis of gastroparesis—a review of experimental andclinical studies. Nat Clin Pract Gastroenterol Hepatol 4(6,2007):336-346].

Despite the fact that at least some aspect each FDIG is different fromthe other FDIG disorders, they nevertheless may share other features,and they are frequently comorbid, so that they may be considered as agroup. Furthermore, symptomatic and pathophysiological aspects thatdifferent FDIGs have in common may make it possible to treat them withsimilar therapeutic methods. Consequently, it is understood that thedevices and methods of the present invention may be applicable to manytypes of FGID, as organized by the Rome III classification: A.Functional esophageal disorders (A1. Functional heartburn; A2.Functional chest pain of presumed esophageal origin; A3. Functionaldysphagia; A4. Globus); B. Functional gastroduodenal disorders (B1.Functional dyspepsia; B1a. Postprandial distress syndrome; B1b.Epigastric pain syndrome; B2. Belching disorders; B2a. Aerophagia; B2b.Unspecified excessive belching; B3. Nausea and vomiting disorders; B3a.Chronic idiopathic nausea; B3b. Functional vomiting; B1c. Cyclicvomiting syndrome; B4. Rumination syndrome in adults or Merycism); C.Functional bowel disorders (C1. Irritable bowel syndrome; C2. Functionalbloating; C3. Functional constipation; C4. Functional diarrhea; C5.Unspecified functional bowel disorder; D. Functional abdominal painsyndrome; E. Functional gallbladder and Sphincter of Oddi (SO) disorders(E1. Functional gallbladder disorder; E2. Functional biliary SOdisorder; E3. Functional pancreatic SO disorder); F. Functionalanorectal disorders (F1. Functional fecal incontinence; F2. Functionalanorectal pain; F2a. Chronic proctalgia; F2a1. Levator ani syndrome;F2a2. Unspecified functional anorectal pain; F2b. Proctalgia fugax; F3.Functional defecation disorders; F3a. Dyssynergic defecation; F3b.Inadequate defecatory propulsion; G. Various GI functional disorders inneonates and toddlers; and H. Various functional GI disorders inchildren and adolescents.

FGIDs account for 41% of diagnoses in GI specialty practices, amongwhich irritable bowel syndrome (IBS) is the most common. IBS comprises12% of the diagnoses made by primary care physicians generally and 28%of the diagnoses in GI practices. Its prevalence is in the range 5-25%,and it accounts for 36% of all visits to gastroenterologists [CHANG L.Review article: epidemiology and quality of life in functionalgastrointestinal disorders. Aliment Pharmacol Ther 20 (Suppl 7,2004):31-39; DROSSMAN D A, Li Z, Andruzzi E, et al. U.S. householdersurvey of functional gastrointestinal disorders. Prevalence,sociodemography, and health impact. Dig Dis Sci. 38(9, 1993):1569-1580;MERTZ H R. Irritable bowel syndrome. N Engl J Med 349(22,2003):2136-2146; CAMILLERI M. Treating irritable bowel syndrome:overview, perspective and future therapies. Br J Pharmacol 141(8,2004):1237-1248; DROSSMAN D A. Review article: an integrated approach tothe irritable bowel syndrome. Aliment Pharmacol Ther 13 (Suppl 2,1999):3-14].

Dyspepsia also has a high prevalence. Patients often experiencedyspeptic symptoms of short duration and mild severity, and aretherefore self-managed, with less than half of dyspepsia sufferersseeking medical care for their complaints. Even so, there are over 2million physician consultations for dyspepsia annually in the UnitedStates alone. Dyspepsia has a prevalence of approximately 25% in Westerncountries, even after the exclusion of individuals with typicalgastro-esophageal reflux disease (GERD) symptoms. The annual incidenceof dyspepsia is approximately 9-10%, and 15% of patients have chronic(>3 months in a year), frequent (>3 episodes per week) often severesymptoms. Functional dyspepsia is the most common cause of dyspepticsymptoms (approximately 75%), with the remainder of dyspepsia caseshaving an organic cause such as a peptic ulcer, reflux disease, etc.[Andrew Seng Boon CHUA. Epidemiology of functional dyspepsia: A globalperspective. World J Gastroenterol 12(17, 2006): 2661-2666; SHAIB Y,El-Serag H B. The prevalence and risk factors of functional dyspepsia ina multiethnic population in the United States. Am J Gastroenterol 99(11,2004):2210-2216; OUSTAMANOLAKIS P, Tack J. Dyspepsia: organic versusfunctional. J Clin Gastroenterol 46(3, 2012):175-90; SANDER G B,Mazzoleni L E, Francesconi C F, et al. Influence of organic andfunctional dyspepsia on work productivity: the HEROES-DIP study. Valuein Health 14(5 Suppl 1, 2011):S126-S129].

A difficulty in interpreting the epidemiological data mentioned above isthat considerable symptomatic and pathophysiological overlap existsbetween FDIG disorders. Thus, despite their classification as differententities, IBS and functional dyspepsia may also be regarded as differentmanifestations of a larger pathophysiological entity that encompasseseven non-FGID disorders with which the FDIG disorders may be comorbid,such as overactive bladder [FRISSORA C L, Koch K L. Symptom overlap andcomorbidity of irritable bowel syndrome with other conditions. CurrGastroenterol Rep 7(4, 2005):264-271; Laura NODDIN, Michael Callahan,and Brian E. Lacy. Irritable Bowel Syndrome and Functional Dyspepsia:Different Diseases or a Single Disorder With Different Manifestations?Med Gen Med 7(3, 2005): 17, pp. 1-10; WANG A, Liao X, Xiong L, Peng S,Xiao Y, Liu S, Hu P, Chen M. The clinical overlap between functionaldyspepsia and irritable bowel syndrome based on Rome III criteria. BMCGastroenterol 8 (2008): 43, pp. 1-7; BALBOA A, Mearin F, Badía X, et al.Impact of upper digestive symptoms in patients with irritable bowelsyndrome. Eur J Gastroenterol Hepatol 18(12, 2006):1271-1277; DEVRIES DR, Van Herwaarden M A, Baron A, Smout A J, Samsom M. Concomitantfunctional dyspepsia and irritable bowel syndrome decreasehealth-related quality of life in gastroesophageal reflux disease. ScandJ Gastroenterol 42(8, 2007):951-956; EVANS P R, Bak Y T, Shuter B,Hoschl R, Kellow J E. Gastroparesis and small bowel dysmotility inirritable bowel syndrome. Dig Dis Sci 42(10, 1997):2087-2093; QUIGLEY EM. Review article: gastric emptying in functional gastrointestinaldisorders. Aliment Pharmacol Ther 20 (Suppl 7, 2004):56-60; ARO P,Talley N J, Ronkainen J, Storskrubb T, Vieth M, Johansson S E,Bolling-Sternevald E, Agréus L. Anxiety is associated withuninvestigated and functional dyspepsia (Rome III criteria) in a Swedishpopulation-based study. Gastroenterology 137(1, 2009):94-100; HSU Y C,Liou J M, Liao S C, Yang T H, Wu H T, Hsu W L, Lin H J, Wang H P, Wu MS. Psychopathology and personality trait in subgroups of functionaldyspepsia based on Rome III criteria. Am J Gastroenterol 104(10,2009):2534-2542; SANTONICOLA A, Siniscalchi M, Capone P, Gallotta S,Ciacci C, Iovino P. Prevalence of functional dyspepsia and its subgroupsin patients with eating disorders. World J. Gastroenterol. 18(32,2012):4379-4385; MATSUZAKI J, Suzuki H, Fukushima Y, Hirata K, FukuharaS, Okada S, Hibi T. High frequency of overlap between functionaldyspepsia and overactive bladder. Neurogastroenterol Motil 24(9,2012):821-827].

Similarly, the distinction between functional dyspepsia andgastroparesis is equivocal. Gastroparesis is a syndrome characterized bydelayed gastric emptying in the absence of mechanical obstruction. Themain symptoms include early satiety, nausea, vomiting, pain, andbloating. In one study, the frequency of symptoms was pain (89%), nausea(93%), early satiety (86%) and vomiting (68%). Gastroparesis is common,affecting up to 5 million individuals in the United States. The majorityof patients are female (80%) and the mean age of onset is 34 years.Between 5 and 12 percent of patients with diabetes have symptoms thatare attributable to gastroparesis [Baha MOSHIREE, Steven Bollipo,Michael Horowitz, and Nicholas J. Talley. Epidemiology of gastroparesis.Chapter 2 (pp. 11-22) In: Gastroparesis. Pathophysiology, Presentationand Treatment. H. P. Parkman and R. W. McCallum, eds. New York: HumanaPress, 2012; JUNG H K, Choung R S, Locke G R 3rd, Schleck C D,Zinsmeister A R, Szarka L A, Mullan B, Talley N J. The incidence,prevalence, and outcomes of patients with gastroparesis in OlmstedCounty, Minnesota, from 1996 to 2006. Gastroenterology 136(4,2009)1225-1233].

Gastroparesis is primarily (but not exclusively) a motility disorder ofthe stomach, in contrast to functional dyspepsia (FD), which is afunctional disorder of the stomach with intertwined sensory and motilityabnormalities. Nevertheless, although gastroparesis and FD are generallyconsidered two distinct disorders, the distinction between them isblurred by the considerable overlap in symptoms and the recognition thatdelayed gastric emptying can be seen in FD. The symptoms of FD aredirectly caused by two major physiological abnormalities—abnormalgastric motility and visceral hypersensitivity—occurring in patients whohave acquired excessive responsiveness to stress as a result of theenvironment during early life, genetic abnormalities, residualinflammation after gastrointestinal infections, or other causes, withthe process modified by factors including psychophysiologicalabnormalities, abnormal secretion of gastric acid, Helicobacter pyloriinfection, diet, and lifestyle. Accordingly, the current (Rome III)diagnostic criteria subdivides FD into two categories—(i) meal-induceddyspeptic symptoms (post-prandial distress syndrome [PDS], characterizedby postprandial fullness and early satiation) and (ii) epigastric painsyndrome ([EPS], characterized by epi-gastric pain and burning). Arationale for the subdivision is that different treatment modalities maybe most suitable for each subgroup: acid suppressive therapy in EPS, andtherapy for PDS in which drugs are used to increase gastrointestinalmovement (prokinetic therapy). Therefore, gastroparesis may be mostclosely associated with the PDS category of functional dyspepsia. Infact, some patients with mild abdominal pain, nausea, postprandialdistress, and evidence of delayed emptying are considered to havefunctional dyspepsia by some clinicians and gastroparesis by others,based on a subjective assessment of how much visceral hypersensitivityversus dysmotility contributes to the symptoms. From a diagnosticstandpoint, a presentation of predominant pain and less nausea isconsidered to be more typical of functional dyspepsia, whereas dominantnausea with minimal pain is more consistent with idiopathicgastroparesis [PARKMAN H P, Camilleri M, Farrugia G, et al.Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMSmeeting. Neurogastroenterol Motil 22(2, 2010):113-133; TALLEY N J, LockeG R 3rd, Lahr B D, Zinsmeister A R, Tougas G, Ligozio G, Rojavin M A,Tack J. Functional dyspepsia, delayed gastric emptying, and impairedquality of life. Gut 55(7, 2006):933-9; KINDT S, Dubois D, Van OudenhoveL, Caenepeel P, Arts J, Bisschops R, Tack J. Relationship betweensymptom pattern, assessed by the PAGI-SYM questionnaire, and gastricsensorimotor dysfunction in functional dyspepsia. NeurogastroenterolMotil 21(11, 2009):1183-1188 and e104-e105; John M. WO and Henry P.Parkman. Motility and Functional Disorders of the Stomach: Diagnosis andManagement of Functional Dyspepsia and Gastroparesis. PracticalGastroenterology. December 2006: 23-48; STANGHELLINI V, De Giorgio R,Barbara G, Cogliandro R, Tosetti C, De Ponti F, Corinaldesi R. DelayedGastric Emptying in Functional Dyspepsia. Curr Treat OptionsGastroenterol 7(4, 2004):259-264].

In the remainder of this background section, current methods fortreating functional dyspepsia and gastroparesis are described. Assummarized here, they include pharmacological methods, the use of herbalmedicines, biofeedback and breathing exercises, hypnosis, acupuncture,direct electrical stimulation of the stomach (gastric electricalstimulation or GES), direct electrical stimulation of the intestine,invasive vagus nerve stimulation, and deep brain stimulation. Asevidenced by the large number of potential treatment methods that are inuse, none of them works reliably, which motivates the new andpotentially better methods that are disclosed here [TALLEY N J, Vakil N;Practice Parameters Committee of the American College ofGastroenterology. Guidelines for the management of dyspepsia. Am JGastroenterol 100(10, 2005):2324-2337; North of England DyspepsiaGuideline Development Group. Dyspepsia. Managing dyspepsia in adults inprimary care. Centre for Health Services Research. University ofNewcastle upon Tyne. 21 Claremont Place. Newcastle upon Tyne. NE2 4AA.UK. 2004, pp. 1-288; SAAD R J, Chey W D. Review article: current andemerging therapies for functional dyspepsia. Aliment Pharmacol Ther24(3, 2006):475-492; HASLER W L. Gastroparesis: symptoms, evaluation,and treatment. Gastroenterol Clin North Am 36(3, 2007):619-647; OlgaHILAS. Management of Gastroparesis. US Pharm 36(12, 2011):HS15-HS18;MASAOKA T, Tack J. Gastroparesis: current concepts and management. GutLiver 3(3, 2009):166-73; WASEEM S, Moshiree B, Draganov P V.Gastroparesis: current diagnostic challenges and managementconsiderations. World J Gastroenterol 15(1, 2009):25-37].

Dietary approaches to treatment involve ingesting multiple small mealseach day and consuming more liquid and less solid. Fatty food andcarbonated beverages are avoided, and for patients who are diabetic,their diet is modified to treat the diabetes.

No drugs with established efficacy are definitive for treatment offunctional dyspepsia and gastroparesis. However, gastrointestinalprokinetic drugs, which stimulate gastric smooth muscle contractions,have long been considered the drugs of choice. Traditional prokineticagents are dopamine-2-receptor (D2) antagonists or 5-HT4 receptoragonists, e.g., cisapride (but now withdrawn from the market),domperidone, metoclopramide, and mosapride. Erythromycin is also used toenhance motility. H2 receptor antagonists, proton pump inhibitors,antiemetics and drugs to treat H. Pylori are also sometimes prescribed[TACK J, Lee K J. Pathophysiology and treatment of functional dyspepsia.J Clin Gastroenterol 39(5 Suppl 3, 2005):S211-6; MONKEMULLER K,Malfertheiner P. Drug treatment of functional dyspepsia. World JGastroenterol 12(17, 2006):2694-2700; HASLER W L. Gastroparesis:symptoms, evaluation, and treatment. Gastroenterol Clin North Am 36(3,2007):619-647].

Alternative medicine approaches are also used to treat functionaldyspepsia and gastroparesis, including the use of herbal medicines,biofeedback, and hypnosis [Thompson COON J, Ernst E. Systematic review:herbal medicinal products for non-ulcer dyspepsia. Aliment PharmacolTher 16(10, 2002):1689-1699; HJELLAND I E, Svebak S, Berstad A, FlataboG, Hausken T. Breathing exercises with vagal biofeedback may benefitpatients with functional dyspepsia. Scand J Gastroenterol 42(9,2007):1054-1062; CALVERT E L, Houghton L A, Cooper P, Morris J, WhorwellP J. Long-term improvement in functional dyspepsia using hypnotherapy.Gastroenterology 123(6, 2002):1778-85].

Acupuncture is also used to treat functional dyspepsia andgastroparesis. The sites of stimulation are usually RN12 (at the middleof the stomach), ST36 (on the front of the leg), PC6 (located on thewrist), and SP6 (on the medial aspect of the lower leg) [TAKAHASHI T.Acupuncture for functional gastrointestinal disorders. J Gastroenterol41(5, 2006):408-417; ZHENG H, Tian X P, Li Y, Liang F R, et al.Acupuncture as a treatment for functional dyspepsia: design and methodsof a randomized controlled trial. Trials 10 (2009):75, pp. 1-9; KIM K H,Kim T H, Choi J Y, Kim J I, Lee M S, Choi S M. Acupuncture forsymptomatic relief of gastroparesis in a diabetic haemodialysis patient.Acupunct Med 28(2, 2010):101-103; WANG C P, Kao C H, Chen W K, Lo W Y,Hsieh C L. A single-blinded, randomized pilot study evaluating effectsof electroacupuncture in diabetic patients with symptoms suggestive ofgastroparesis. J Altern Complement Med 14(7, 2008):833-839; IMAI K,Ariga H, Chen C, Mantyh C, Pappas T N, Takahashi T. Effects ofelectroacupuncture on gastric motility and heart rate variability inconscious rats. Auton Neurosci 138(1-2, 2008):91-98]. Despite the factthat a vagus nerve is not stimulated by the acupuncture as currentlypracticed, vagal activity is nevertheless said to be indirectly affected[OUYANG H, Yin J, Wang Z, Pasricha P J, Chen J D. Electroacupunctureaccelerates gastric emptying in association with changes in vagalactivity. Am J Physiol Gastrointest Liver Physiol 282(2,2002):G390-G396].

Various devices have been used or proposed to treat functionalgastrointestinal disorders and gastroparesis [GREENWAY F, Zheng J.Electrical stimulation as treatment for obesity and diabetes. J DiabetesSci Technol 1(2, 2007):251-259]. The most well known among them isgastric electrical stimulation (GES), which stimulates stomach muscledirectly, in a manner that is analogous to a cardiac pacemaker.Low-frequency/high-energy GES appears to work well in principle, but itis not presently suitable for routine clinical use.High-frequency/low-energy GES does not significantly modify gastric slowwave and motor activity and does not appear to consistently resolve theproblem of delayed gastric emptying, but may it nevertheless resolvesome symptoms. Therefore, GES is considered at best partially successfulin treating gastroparesis [Mauro BORTOLOTTI. Gastric electricalstimulation for gastroparesis: A goal greatly pursued, but not yetattained. World J Gastroenterol 17(3, 2011): 273-282; McCALLUM R W,Dusing R W, Sarosiek I, Cocjin J, Forster J, Lin Z. Mechanisms ofsymptomatic improvement after gastric electrical stimulation ingastroparetic patients. Neurogastroenterol Motil 22(2, 2010):161-167,e50-e51; YIN J, Abell T D, McCallum R W, Chen J D. Gastricneuromodulation with Enterra system for nausea and vomiting in patientswith gastroparesis. Neuromodulation 15(3, 2012):224-231; SOFFER E, AbellT, Lin Z, Lorincz A, McCallum R, Parkman H, Policker S, Ordog T. Reviewarticle: gastric electrical stimulation for gastroparesis—physiologicalfoundations, technical aspects and clinical implications. AlimentPharmacol Ther 30(7, 2009):681-694; SONG G Q, Chen JD. Synchronizedgastric electrical stimulation improves delayed gastric emptying innonobese mice with diabetic gastroparesis. J Appl Physiol 103(5,2007):1560-1564; LIU J, Qiao X, Chen J D. Vagal afferent is involved inshort-pulse gastric electrical stimulation in rats. Dig Dis Sci 49(5,2004):729-737; CHEN J H, Song G Q, Yin J, Sun Y, Chen J D. Gastricelectrical stimulation reduces visceral sensitivity to gastricdistention in healthy canines. Auton Neurosci 160(1-2, 2011):16-20;OGRADY G, Egbuji J U, Du P, Cheng L K, Pullan A J, Windsor J A.High-frequency gastric electrical stimulation for the treatment ofgastroparesis: a meta-analysis. World J Surg 33(8, 2009)1693-1701]. GESis also disclosed in the patent literature, for example: U.S. Pat. No.8,239,027, entitled Responsive gastric stimulator, to IMRAN; and U.S.Pat. No. 7,363,084, entitled Device for electrically stimulatingstomach, to KUROKAWA et al.

In some patients, delayed emptying of the stomach may be due in part todelayed movement of chyme in the intestine, i.e., a downstreambacking-up, such that intestinal movement that is promoted by electricalstimulation of the intestine itself may indirectly promote gastricemptying [XU J, Chen J D. Intestinal electrical stimulation improvesdelayed gastric emptying and vomiting induced by duodenal distension indogs. Neurogastroenterol Motil 20(3, 2008):236-42]. As described below,a related mechanism is invoked by KNUDSEN et al in the form of “entericrhythm management”, wherein invasive vagus nerve stimulation is used topromote the effects of pancreatic exocrine secretion and bile on thecomposition and the digestion of intraduodenal chyme, thereby indirectlypromoting gastric emptying through downstream effects. The presentinvention uses noninvasive rather than invasive vagus nerve stimulation,and physiological differences as compared with the KNUDSEN disclosurealso arise because the present invention stimulates the vagus nerve at adifferent location and involves different mechanisms, but it isunderstood that the present invention might also produce suchcoordinated effects throughout the gastrointestinal system, thereby alsounderscoring the overlap between different forms of functionalgastrointestinal disorders.

Deep brain electrical stimulation has also been used in connection withgastrointestinal problems, but only in conjunction with the treatment ofanother problem such as parkinsonism [ARAI E, Arai M, Uchiyama T, et al.Subthalamic deep brain stimulation can improve gastric emptying inParkinson's disease. Brain 135 (Pt 5, 2012):1478-1485].

Magnetic stimulation of patients with gastrointestinal disorders hasapparently not been performed for dyspepsia or gastroparesis, althoughit has been performed for lower digestive problems (on the buttocks) andfor visceral pain (at the cerebral cortex) [LEE K J, Kim J H, Cho S W.Short-term effects of magnetic sacral dermatome stimulation foridiopathic slow transit constipation: sham-controlled, cross-over pilotstudy. J Gastroenterol Hepatol 21(1 Pt 1, 2006):47-53; LEFAUCHEUR J P.Use of repetitive transcranial magnetic stimulation in pain relief.Expert Rev Neurother 8(5, 2008):799-808].

The literature on vagus nerve stimulation (VNS) generally teaches thatits use may produce adverse gastrointestinal side effects, which is tosay, most of the VNS literature teaches away from the present invention.Thus, nausea (14-20%), vomiting (13-18%) and dyspepsia (12-18%) arecommonly reported adverse effects from implanted vagus nerve stimulatorsthat are used to treat epilepsy and/or depression, although theside-effects are generally mild and usually do not warrant terminationof the therapy. The prevalence of the side effects depends upon theparameters of the nerve stimulation (frequency, pulse-width, etc.).There is also one case report in which chronic diarrhea was associatedwith VNS, such that the diarrhea ceased after VNS therapy was terminated[HATTON K W, McLarney J T, Pittman T, Fahy B G. Vagal nerve stimulation:overview and implications for anesthesiologists. Anesth Analg 103(5,2006):1241-1249; SANOSSIAN N, Haut S. Chronic diarrhea associated withvagal nerve stimulation. Neurology 58 (2002):330].

Nevertheless, SINCLAIR reported one clinical case demonstrating thatinvasive VNS might offer an alternative solution to dyspepsia resultingfrom impaired gastric emptying, or at least a treatment for symptoms ofreflux [Rohna SINCLAIR and Rahul R. Bajekal. Vagal Nerve Stimulation andReflux. Anesthesia & Analgesia 105(3, 2007): 884-885]. Invasive VNS totreat gastrointestinal conditions is also described in several patents.In U.S. Pat. No. 5,540,730, entitled Treatment of motility disorders bynerve stimulation, to TERRY, Jr. et al., stimulation of a vagus nerve inthe vicinity of the patient's stomach is performed in response to theimpedance of a selected part of the gastrointestinal system (as anindication of gastrointestinal status), in order to treat hypomobilityor hypermobility. In U.S. Pat. No. 7,167,751, entitled Method of using afully implantable miniature neurostimulator for vagus nerve stimulationto WHITEHURST et al. it is disclosed that: “As another example, thevagus nerve may be stimulated to relieve gastrointestinal disorders(such as including gastroesophageal reflux disease (GERD), fecaldysfunction, gastrointestinal ulcer, gastroparesis, and othergastrointestinal motility disorders.” In U.S. Pat. No. 7,856,273,entitled Autonomic nerve stimulation to treat a gastrointestinaldisorder, to MASCHINO et al., a vagus nerve is electrically stimulatedin order to treat a gastrointestinal disorder that may include amotility disorder. Invasive vagus nerve stimulation has also beencombined with gastric electrical stimulation (GES) [U.S. Pat. No.6,826,428, entitled Gastrointestinal electrical stimulation, to CHEN etal.].

In a series of patents and patent applications, KNUDSON and colleaguesalso describe invasive methods in which a vagus nerve is electricallystimulated in order to treat a variety of functional gastrointestinaldisorders [All to KNUDSON et al. —U.S. Pat. No. 8,046,085, entitledControlled vagal blockage therapy; U.S. Pat. No. 8,010,204, entitledNerve blocking for treatment of gastrointestinal disorders; U.S. Pat.No. 7,986,995, entitled Bulimia treatment; U.S. Pat. No. 7,729,771,entitled Nerve stimulation and blocking for treatment ofgastrointestinal disorders; U.S. Pat. No. 7,720,540, entitledPancreatitis treatment; U.S. Pat. No. 7,693,577, entitled Irritablebowel syndrome treatment; U.S. Pat. No. 7,630,769, entitled G Iinflammatory disease treatment; U.S. Pat. No. 7,489,969, entitled Vagaldown-regulation obesity treatment; U.S. Pat. No. 7,444,183, entitledIntraluminal electrode apparatus and method; U.S. Pat. No. 7,167,750,entitled Obesity treatment with electrically induced vagal downregulation; U.S. Pat. No. 7,844,338, entitled High frequency obesitytreatment; U.S. Pat. No. 7,613,515, entitled High frequency vagalblockage therapy; US 20040176812, entitled Enteric rhythm management; US20040172085, entitled Nerve stimulation and conduction block therapy].These patents and applications differ from the present invention inseveral significant ways, including: they involve invasive methods,whereas the present invention involves noninvasive methods; in thosepatents, the site of vagus nerve stimulation is below a vagalinnervation of the heart, e.g. a few centimeters below the diaphragm andproximal to stomach and pancreo/biliary innervation or around aninternal body organ, whereas the present invention stimulates a vagusnerve at the neck, such that different vagal nerve fibers are stimulatedin the present invention; stimulation in the present invention maygenerate proximate effects within the central nervous system (e.g.,increasing afferent activity in A and B fibers of the vagus nerve toincrease the levels of inhibitory neurotransmitters in the brainstem),whereas they produce their proximate effects within a gastrointestinalend organ through efferent nerves; they generally involve the use of oneor more blocking electrodes (functionally speaking, a reversiblevagotomy, wherein the block at least partially prevents nervetransmission across the site of the block), whereas the presentinvention does not; the present invention makes use of a burstingsinusoidal stimulation signal, whereas they do not; with regard toeffects on gastric emptying, the present invention modulates theactivity of interstitial cells of Cajal, whereas they do not; thepresent invention may modify resting state neural networks in the brainthat are related to interoception, whereas they do not disclose any suchmechanism. Many of these same distinctions apply to the other previouslymentioned invasive VNS patents as well.

There also exists literature concerning noninvasive electricalstimulation methods as they relate to gastrointestinal disorders.Noninvasive methods have been described to treat symptoms that mayaccompany functional gastrointestinal disorders, e.g., nausea andvomiting. U.S. Pat. No. 4,865,048, entitled Method and apparatus fordrug free neurostimulation, to ECKERSON, teaches electrical stimulationof a branch of the vagus nerve behind the ear on the mastoid processes,in order to treat symptoms of drug withdrawal that may include nauses(sic) and vomiting. In patent publication US20080208266, entitled Systemand method for treating nausea and vomiting by vagus nerve stimulation,to LESSER et al., electrodes are used to stimulate the vagus nerve inthe neck to reduce nausea and vomiting, or can be arranged near thechest or abdomen, so as to stimulate the esophagus, stomach, duodenum orintestines. However, because these methods are intended to treat morningsickness, side-effects of chemotherapy, etc., they are not designedspecifically for treating for the forms of nausea and vomiting that aredue to dyspepsia, gastroparesis, or other functional gastrointestinaldisorders and do not simultaneously treat other symptoms of thosedisorders such as bloating. Consequently, those methods are intended totreat nausea and vomiting, but not a gastrointestinal disorder per se.For example, patients with gastroparesis, cyclic vomiting syndrome, andrumination syndrome may all experience different forms of vomiting, butthe ECKERSON and the LESSER disclosures do not suggest which, if any, ofthese disorders may be treated by their methods. Furthermore, they teachdevices and stimulation parameters that differ from what is disclosedhere.

In contrast, WEINKAUF and colleagues used transcutaneous electricalstimulation to treat true gastroparesis. However, unlike the presentinvention, the electrical stimulation was performed on the back of thepatients and did not involve the vagus nerve [WEINKAUF J G, YiannopoulosA, Faul J L. Transcutaneous electrical nerve stimulation for severegastroparesis after lung transplantation. J Heart Lung Transplant. 24(9,2005):1444.e1-e3]. Similarly, KOKLU and colleagues used transcutaneousinterferential current electrical stimulation to treat dyspepticpatients. However, also unlike the present invention, the electricalstimulation was performed on the back of the patients and did notinvolve stimulating a selected vagus nerve [KOKLUS, Köklü G, Ozgüçlü E,Kayani G U, Akbal E, Hasçelik Z. Clinical trial: interferential electricstimulation in functional dyspepsia patients—a prospective randomizedstudy. Aliment Pharmacol Ther 31(9, 2010):961-968]. Patent publicationUS20100249859, entitled Methods for autonomic neuromodulation for thetreatment of systemic disease, to DiLorenzo, discloses that “Modulation[of cranial nerves] is performed to modulate . . . gastroparesis, andother disorders.”He includes noninvasive techniques among those used forneural modulation, but described them only as being the use of tactilestimulation, including light touch, pressure, vibration, and othermodalities that may be used to activate the peripheral or cranialnerves. BALAJINS also describes noninvasive stimulation of the vagusnerve in the context of gastroenterology, but the stimulation involvessham feeding rather than electrical stimulation [BALAJI N S, Crookes PF, Banki F, Hagen J A, Ardill J E, DeMeester T R. A safe and noninvasivetest for vagal integrity revisited. Arch Surg 137(8, 2002): 954-958;LUNDING J A, Nordström L M, Haukelid A O, Gilja O H, Berstad A, HauskenT. Vagal activation by sham feeding improves gastric motility infunctional dyspepsia. Neurogastroenterol Motil 20(6, 2008):618-624]. Inview of the foregoing, noninvasive electrical stimulation of a vagusnerve at the neck has not been performed to treat gastroparesis,functional dyspepsia, or other functional gastrointestinal conditions,despite the aforementioned potential advantages of noninvasive methodsas compared with invasive methods.

In a commonly assigned, co-pending patent application, US20110125203,entitled Magnetic Stimulation Devices and Methods of Therapy, to SIMONet al., Applicants teach the use of a magnetic stimulation device, suchas the ones disclosed here, to stimulate a vagus nerve in the neck totreat postoperative ileus, which is a form of hypomotility of thegastrointestinal tract in the absence of mechanical bowel obstruction.In that application, Applicants also teach use of a magnetic stimulationdevice to treat sphincter of Oddi dysfunction by stimulating a nerveplexus of fibers emanating from the tenth cranial nerve (the vagusnerve). In another commonly assigned, co-pending patent application,US20120101326, entitled Non-invasive electrical and magnetic nervestimulators used to treat overactive bladder and urinary incontinence,to SIMON et al., applicants disclose the use of electrical nervestimulation to affect pacemaker cells in the bladder that resemble thepacemaker cells in the stomach (interstitial cells of Cajal). Thepresent disclosure extends those teachings to include additional methodsand devices for the treatment or prevention of functionalgastrointestinal disorders and gastroparesis.

SUMMARY OF THE INVENTION

The present invention involves devices and methods for the treatment ofgastroparesis, functional dyspepsia, or other functionalgastrointestinal disorders. In certain aspects of the invention, adevice or system comprises an energy source of magnetic and/orelectrical energy that is transmitted non-invasively to, or in closeproximity to, a selected nerve of the patient to temporarily stimulateand/or modulate the signals in the selected nerve. In preferredembodiments of the invention, the selected nerve is a vagus nerve in thepatient's neck.

Injury or loss of interstitial cells of Cajal (ICC) is the single mostcommon pathophysiological feature found in patients with gastroparesisand other motility disorders of the gastrointestinal system. The ICCinjury or loss may be due to a deficiency of trophic factors necessaryfor normal ICC maturation and survival. The present invention providesrequisite trophic factors to gastric ICC cells and their progenitors,through electrical stimulation of a vagus nerve. In particular, itprovides trophic factors to the ICC that are associated withintramuscular arrays, which are mechanoreceptors that are connected tovagus afferent nerve fibers. A method of the invention involveselectrical stimulation of vagus afferent nerve fibers so as to imitateafferent signals that would have been transmitted by the vagal afferentsin a normal individual. According to the invention, the afferent vagusnerve fiber will respond by providing to the damaged ICC what would havebeen the normal trophic factors, thereby reversing ICC degradation orloss, and as a consequence improving gastric motility.

Gastroparesis and functional dyspepsia are accompanied by abnormalinteroception and visceral hypersensitivity. A method is disclosed thattargets a front end of the interoceptive neural pathways, comprising thenucleus tractus solitarius, area postrema, and dorsal motor nucleus. Thearea postrema is well known as the medullary structure in the brain thatcontrols vomiting, but it plays a more general role in mediatingintroceptive sensations, comprising also such sensations as postprandialfullness, bloating, pain, and nausea. Electrical stimulation of A and Bfibers alone of the vagus nerve (using special stimulation waveforms anddevices) produces increased levels of inhibitory neurotransmitters inthe brainstem, which decreases signals that are conveyed to theparabrachial nucleus, VMb and VMpo of the interoceptive neural pathways.This inhibition is accomplished by causing the periaqueductal gray,raphe nucei, and locus ceruleus to release inhibitory neurotransmittersGABA, and/or serotonin, and/or norepinephrine, respectively, into thenucleus tractus solitarius, thereby opposing glutamate-mediatedactivation of the area postrema and dorsal motor nucleus by the nucleustractus solitarius. Inhibition of the dorsal motor nucleus by theseneurotransmitters also causes decreased neuronal activity in the areapostrema, thereby leading to a reduction in abnormal interoception andvisceral hypersensitivity.

The brain contains several neural networks that can be identified bybrain imaging, which are known as resting state networks. Examples ofsuch networks include the default mode network (DMN), the ventralattention network (VAN), and networks that include the anterior insula(AI) and anterior cingulate cortex (ACC). The AI/ACC networks areclosely associated with interoception, which may be abnormal in patientswith gastroparesis, functional dyspepsia, and other functionalgastrointestinal disorders. The locus ceruleus is thought to project toall of the resting state networks. Vagus stimulation methods of thepresent invention increase norepinephrine levels in a resting statenetwork, wherein a particular resting state network may bepreferentially stimulated via the locus ceruleus, by using a vagus nervestimulation waveform that entrains to the signature EEG pattern of thatnetwork. Depending on the distribution of adrenergic receptor subtypeswithin the resting state network, the vagus nerve stimulation maydeactivate or activate the network. Deactivation of a resting statenetwork may also be accomplished by activating another resting statenetwork, which causes deactivation of other networks. According to theinvention, AI/ACC-containing resting state networks may be deactivatedeither directly via the locus ceruleus or indirectly via activation ofanother resting network. In either case, deactivation of theAI/ACC-containing resting state network will diminish interoceptivesymptoms of gastroparesis and/or functional dyspepsia. It is understoodthat all the above-mentioned mechanisms may apply to the treatment ofother functional disorders as well.

For some patients, the stimulation may be performed for 30 minutes, andthe treatment is performed several times a week for 12 weeks or longer,because the disease is a chronic situation that requires a substantialperiod to reverse the pathophysiology. For patients experiencingintermittent symptoms, the treatment may be performed only when thepatient is symptomatic. However, it is understood that parameters of thestimulation protocol may be varied in response to heterogeneity in thepathophysiology of patients. Different stimulation parameters may alsobe selected as the course of the patient's disease changes. In preferredembodiments, the disclosed methods and devices do not produce clinicallysignificant side effects, such as agitation or anxiety, or changes inheart rate or blood pressure.

In one embodiment, the method of treatment includes positioning the coilof a magnetic stimulator non-invasively on or above a patient's neck andapplying a magnetically-induced electrical impulse non-invasively to thetarget region within the neck to stimulate or otherwise modulateselected nerve fibers. In another embodiment, surface electrodes areused to apply electrical impulses non-invasively to the target regionwithin the neck to likewise stimulate or otherwise modulate selectednerve fibers. Preferably, the target region is adjacent to, or in closeproximity with, the carotid sheath that contains a vagus nerve.

The non-invasive magnetic stimulator device is used to modulateelectrical activity of a vagus nerve, without actually introducing amagnetic field into the patient. The preferred stimulator comprises twotoroidal windings that lie side-by-side within separate stimulatorheads, wherein the toroidal windings are separated by electricallyinsulating material. Each toroid is in continuous contact with anelectrically conducting medium that extends from the patient's skin tothe toroid. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described below,shaping an elongated electrical field of effect.

In another embodiment of the invention, the stimulator comprises asource of electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve. The stimulator may comprise twoelectrodes that lie side-by-side within a hand-held enclosure, whereinthe electrodes are separated by electrically insulating material. Eachelectrode is in continuous contact with an electrically conductingmedium that extends from the interface element of the stimulator to theelectrode. The interface element also contacts the patient's skin whenthe device is in operation.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of about 0 to 30 volts. The current ispassed through the electrodes in bursts of pulses. There may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 20 to 1000 microseconds, preferably 200microseconds. A burst followed by a silent inter-burst interval repeatsat 1 to 5000 bursts per second (bps, similar to Hz), preferably at 15-50bps, and even more preferably at 25 bps. The preferred shape of eachpulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m (preferablyless than 100 V/m) and an electrical field gradient of greater than 2V/m/mm. Electric fields that are produced at the vagus nerve aregenerally sufficient to excite all myelinated A and B fibers, but notnecessarily the unmyelinated C fibers. However, by using a reducedamplitude of stimulation, excitation of A-delta and B fibers may also beavoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

Treating or averting symptoms of gastroparesis and/or functionaldyspepsia may be implemented within the context of control theory. Acontroller comprising, for example, one of the disclosed vagus nervestimulators, a PID, and a feedforward model, provides input to thepatient via stimulation of one or both of the patient's vagus nerves.Feedforward models may be black box models, particularly models thatmake use of support vector machines. Data for training and exercisingthe models are from noninvasive physiological and/or environmentalsignals obtained from sensors located on or about the patient. The modelpredicts the onset of symptoms, which may be avoided prophylacticallythrough use of vagus nerve stimulation. If the symptoms are in progress,the vagus nerve stimulation may terminate them.

The novel systems, devices and methods for treating gastroparesis andfunctional dyspepsia are more completely described in the followingdetailed description of the invention, with reference to the drawingsprovided herewith, and in claims appended hereto. Other aspects,features, advantages, etc. will become apparent to one skilled in theart when the description of the invention herein is taken in conjunctionwith the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 shows structures within a patient's stomach and nervous systemthat may be abnormal in gastroparesis and/or functional dyspepsia, thephysiology of which may be modulated by electrical stimulation of avagus nerve.

FIG. 2A is a schematic view of a nerve modulating device according tothe present invention which supplies controlled pulses of electricalcurrent to a magnetic stimulator coil.

FIG. 2B is a schematic view of a nerve modulating device according tothe present invention which supplies controlled pulses of electricalcurrent to surface electrodes.

FIG. 2C illustrates an exemplary electrical voltage/current profile forthe present invention.

FIG. 2D illustrates an exemplary waveform for modulating impulses thatare applied to a nerve according to the present invention.

FIG. 2E illustrates another exemplary waveform for modulating impulsesthat are applied to a nerve according to the present invention.

FIG. 3A is a perspective view of the top of a dual-toroid magneticstimulator coil according to an embodiment of the present invention.

FIG. 3B is a perspective view of the bottom of the dual-toroid magneticstimulator coil of FIG. 3A.

FIG. 3C is a cut-a-way view of the stimulator coil of FIG. 3A.

FIG. 3D is a cut-a-way view of the stimulator coil of FIG. 3B.

FIG. 3E is an alternative embodiment illustrating the stimulator coil ofFIGS. 3A-3D attached to a separate power source.

FIG. 4A is a perspective view of a dual-electrode stimulator accordingto another embodiment of the present invention.

FIG. 4B is a cut-a-way view of the stimulator of FIG. 4A.

FIG. 4C illustrates a head of the stimulator of FIG. 4A.

FIG. 4D is a cut-a-way view of the head of FIG. 4C.

FIG. 5A is a perspective view of the top of a dual-electrode stimulatoraccording to yet another embodiment of the present invention.

FIG. 5B is a perspective view of the bottom of the stimulator of FIG.5B.

FIG. 5C is a cut-a-way view of the stimulator of FIG. 5A.

FIG. 5D is a cut-a-way view of the stimulator of FIG. 5B.

FIG. 6 illustrates the approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of a patient.

FIG. 7 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment, a time-varying magnetic field, originating andconfined to the outside of a patient, generates an electromagnetic fieldand/or induces eddy currents within tissue of the patient. In anotherembodiment, electrodes applied to the skin of the patient generatecurrents within the tissue of the patient. An objective of the inventionis to produce and apply electrical impulses that interact with thesignals of one or more nerves to achieve the therapeutic result ofaltering the course of gastroparesis, functional dyspepsia, and/or otherfunctional gastrointestinal disorders. Much of the disclosure will bedirected specifically to treatment of a patient by electromagneticstimulation in or around a vagus nerve, with devices positionednon-invasively on or near a patient's neck. In particular, the presentinvention can be used to stimulate or otherwise modulate the activity ofnerves that connect to certain structures and cells in the stomach,including intramuscular array (IMA) mechanoreceptors, interstitial cellsof Cajal (ICC), and neurons of the enteric nervous system (ENS), as wellas to modulate the activity of peripheral and central nerves thatparticipate in interoception. However, it will be appreciated that thedevices and methods of the present invention can be applied to othertissues and nerves of the body, including but not limited to otherparasympathetic nerves, sympathetic nerves, spinal or cranial nerves. Asrecognized by those having skill in the art, the methods should becarefully evaluated prior to use in patients known to have preexistingcardiac issues.

Topics that are presented below in connection with the disclosure of theinvention include the following: (1) Overview of physiologicalmechanisms by which vagus nerve stimulation may modulate the activity ofnerves that connect to certain structures and cells in the stomach,including intramuscular array (IMA) mechanoreceptors, interstitial cellsof Cajal (ICC), and neurons of the enteric nervous system (ENS), as wellas modulate the activity of peripheral and central nerves thatparticipate in interoception, thereby altering the course ofgastroparesis, functional dyspepsia, and/or other functionalgastrointestinal disorders; (2) Description of Applicant's magnetic andelectrode-based nerve stimulating devices, describing in particular theelectrical waveform used to stimulate a vagus nerve; (3) Preferredembodiments of the magnetic stimulator; (4) Preferred embodiments of theelectrode-based stimulator; (5) Application of the stimulators to theneck of the patient; (6) Use of the devices with feedback andfeedforward to improve treatment of individual patients.

Overview of Physiological Mechanisms Through which the Disclosed VagusNerve Stimulation Methods May be Used to Treat Patients withGastroparesis and Functional Dyspepsia

The present invention discloses methods and devices for electricallystimulating a vagus nerve noninvasively, in order to treat a patient forgastroparesis, functional dyspepsia, and/or other functionalgastrointestinal conditions. FIG. 1 shows the location of thestimulation as “Vagus Nerve Stimulation,” relative to connections withother anatomical structures that are affected by the stimulation [HOLZERP, Schicho R, Holzer-Petsche U, Lippe I T. The gut as a neurologicalorgan. Wien Klin Wochenschr 113(17-18, 2001):647-660]. Physiologicalmechanisms that are involved, according to the invention, are describedin the paragraphs that follow.

The vagus nerve (tenth cranial nerve, paired left and right) is composedof motor and sensory fibers. The vagus nerve leaves the cranium, passesdown the neck within the carotid sheath to the root of the neck, thenpasses to the chest and abdomen, where it contributes to the innervationof the viscera, including the stomach.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system. Propagation of electrical signals in efferentand afferent directions are indicated by arrows in FIG. 1. Ifcommunication between structures is bidirectional, this is shown in FIG.1 as a single connection with two arrows, rather than showing theefferent and afferent nerve fibers separately.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra. Most of the afferent connectionsfrom the gastrointestinal system involve the nodose ganglion.

Trophic substances may move within an axon in a direction opposite tothe direction of electrical impulse propagation (anterograde axonaltransport for afferent nerves, i.e, from nerve nucleus towards theperiphery; retrograde axonal transport for efferent nerves, i.e, fromperiphery to nerve nucleus). For example, trophic substances may movetowards the structure labeled as IMA in FIG. 1, along themechanoreceptor afferent nerve having a cell body located in the nodoseganglion. According to the present invention, whether that nerve iselectrically stimulated normally through the sensation of movementwithin the stomach, or by external electrical stimulation as in thepresent invention, that stimulation may cause trophic factors to reachthe IMA to maintain, protect, or promote the structural integrity of theIMA and nearby objects, such as cells in what is labeled in FIG. 1 as“ICC network.”

Vagal afferents traverse the brainstem in the solitary tract, with someeighty percent of the terminating synapses being located in the nucleusof the tractus solitarius (or nucleus tractus solitarii, nucleus tractussolitarius, or NTS, see FIG. 1). The NTS projects to a wide variety ofstructures in the central nervous system, such as the amygdala, raphenuclei, periaqueductal gray, nucleus paragigantocellurlais, olfactorytubercule, locus ceruleus, nucleus ambiguus and the hypothalamus. TheNTS also projects to the parabrachial nucleus, which in turn projects tothe hypothalamus, the thalamus, the amygdala, the anterior insula, andinfralimbic cortex, lateral prefrontal cortex, and other corticalregions [JEAN A. The nucleus tractus solitarius: neuroanatomic,neurochemical and functional aspects. Arch Int Physiol Biochim Biophys99(5, 1991):A3-A52]. Such central projections are discussed below inconnection with the gut-brain axis and interoception.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections (see FIG. 1), controls parasympatheticfunction primarily below the level of the diaphragm, while the ventralvagal complex, comprised of nucleus ambiguus and nucleus retrofacial,controls functions primarily above the diaphragm in organs such as theheart, thymus and lungs, as well as other glands and tissues of the neckand upper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus, which is relevant to potential cardiovascular sideeffects that may be produced by vagus nerve stimulation.

In order to describe mechanisms by which the disclosed non-invasivevagus nerve stimulation may be used to treat gastroparesis and/orfunctional dyspepsia, we first summarize the relevant anatomy andinnervation of the stomach, including innervation by the parasympatheticand sympathetic nervous systems [Arthur C. GUYTON and John E. Hall.General Principles of Gastrointestinal Function—Motility, NervousControl, and Blood Circulation. pp. 771-778. In: Textbook of medicalphysiology, 11th ed. Philadelphia: Elsevier Saunders, 2006; Bruce MKOEPPEN and Bruce A Stanton. The gastric phase of the integratedresponse to a meal. Chapter 28 (pp. 504-515) in Berne & Levy physiology,6th Edition. St. Louis, Mo.: Elsevier Mosby, 2010].

The stomach is a J-shaped tube with two openings (cardiac and pyloricorifices, opening to the esophagus and duodenum, respectively), twocurvatures (greater and lesser), and two surfaces (anterior andposterior). The top of the stomach, the fundus, is dome shaped and isusually full of gas. The body (corpus) of the stomach lies below thefundus, and it connects to the lower pyloric region of the stomach(pyloric antrum and canal). Parasympathetic innervation of the stomachis supplied by branches of the vagus nerve. The anterior vagal trunk isa branch of the vagus nerve that contributes to the esophageal plexus.It consists primarily of fibers from the left vagus, but also contains afew fibers from the right vagus. The anterior gastric branches ofanterior vagal trunk supply the stomach. One of its long branches runsfrom the lesser curvature of the stomach as far as the pyloric antrum tofan out into branches like the digits of a crow's foot to supply thepyloric antrum and the anterior wall of pyloric canal. The posteriorvagal trunk is a branch of the vagus nerve that also contributes to theesophageal plexus. It consists primarily of fibers from the right vagus,but also contains a few fibers from the left vagus. The posteriorgastric branches of the posterior vagal trunk supplies innervation tothe posterior surface of stomach. Thus, electrical stimulation of theleft versus right vagus nerve will preferentially stimulate particularregions of the stomach.

Various structures of the stomach are innervated by these vagalbranches. Proceeding from the lumen of the stomach outward, the wall ofthe stomach comprises an inner mucosa (epithelium, lamina propria, andmuscularis mucosae), a layer of fibrous connective tissue (submucosa,with innervation forming Meissner's plexus, also known as the submucosalplexus, and with a circulatory arteriolar and venous plexus), layers ofsmooth muscle (oblique, circular, and circular layers, with innervationbetween the latter layers forming Auerbach's plexus, also known as themyenteric plexus), and a serosal layer of connective tissue that iscontinuous with the surrounding peritoneum. The mucosa is densely packedwith gastric glands, which contain cells that produce mucus, gastricacid, intrinsic factor, pepsinogen, gastrin, cholecystokinin,somatostatin, etc., that protect the stomach, aid in digestion, andsignal digestive status within the stomach and to the rest of the body.

Gastric contractions and secretions are controlled in large measure by asemi-autonomous local nervous system (the enteric nervous system or ENS,also known as the intrinsic nervous system, see FIG. 1), comprising theabove-mentioned submucosal plexus (Meissner's plexus) and myentericplexus (Auerbach's plexus). The myenteric plexus controls mainly stomachwall movements, and the submucosal plexus controls mainly secretion andlocal blood flow. There are also minor plexuses beneath the serosa,within the circular smooth muscle and in the mucosa. These entericplexuses connect to one another, as well as to extrinsic sympathetic andparasympathetic nerve fibers that can enhance or inhibit gastric musclecontractions and secretions. The enteric nervous system extends theentire length of the gastrointestinal system, thereby providing forphysiological coordination between organs.

The enteric nervous system contains all the neuron types needed toperform independent reflex activity, even when it is dissociated fromexternal sensory input or interaction with the sympathetic andparasympathetic nervous systems. Enteric sensory neurons receiveinformation from sensory receptors in the mucosa and muscle. At leastfive different sensory receptors have been identified in the mucosa,which respond to mechanical, thermal, osmotic and chemical stimuli.Motor neurons within the enteric plexuses control gastrointestinalmotility and secretion. Enteric interneurons integrate information fromsensory neurons and use that information to control enteric motorneurons. The functional and chemical diversity of enteric neuronsclosely resembles that of the central nervous system. Furthermore, glialcells are an integral component of the enteric nervous system, and theyoutnumber enteric neurons. Consequently, the enteric nervous system maybe regarded as a displaced part of the central nervous system thatretains communication with the brain through sympathetic andparasympathetic afferent and efferent neurons [GOYAL R K, Hirano I. Theenteric nervous system. N Engl J Med 334 (17, 1996):1106-1115;SURPRENANT A. Control of the gastrointestinal tract by enteric neurons.Annu Rev Physiol. 56 (1994):117-140; Marcello COSTA, John B Furness.Structure and Neurochemical Organization of the Enteric Nervous System.Compr Physiol 2011, Supplement 17: Handbook of Physiology, TheGastrointestinal System, Neural and Endocrine Biology (first published1989): 97-109; SCHEMANN M. Control of gastrointestinal motility by the“gut brain”—the enteric nervous system. J Pediatr Gastroenterol Nutr41(Suppl 1, 2005):54-6; BAGYANSZKI M, Bodi N. Diabetes-relatedalterations in the enteric nervous system and its microenvironment.World J Diabetes 3(5, 2012):80-93; GULBRANSEN B D, Sharkey K A. Novelfunctional roles for enteric glia in the gastrointestinal tract. Nat RevGastroenterol Hepatol 9(11, 2012):625-632].

Sensory nerve endings that originate in the gastric epithelium orstomach wall send afferent fibers to plexuses of the enteric system asdescribed above, as well as to the vagus nerves. They also send fibersto the pre-vertebral ganglia of the sympathetic nervous system and tothe spinal cord (See FIG. 1). Vagal afferents consist of two majortypes: mechanoreceptors which act largely as in-series tensionreceptors, and mucosal receptors which respond to mechanical stimulationof the mucosa and to a range of chemicals, mediators and nutrients.Vagal afferent axons ramify extensively, filling the enteric plexuseswith plates of endings (intraganglionic laminar endings) andinfiltrating muscle sheets (intramuscular arrays coursing withinterstitial cells of Cajal). Parasympathetic afferent signals arecentral to vago-vagal reflexes that control gastric motility andsecretion, and sympathetic afferent signals are important in regards tothe sensation of gastric pain, as described below [BERTHOUD H R,Neuhuber W L. Functional and chemical anatomy of the afferent vagalsystem. Auton Neurosci 85(1-3, 2000):1-17; BLACKSHAW L A, Brookes S J,Grundy D, Schemann M. Sensory transmission in the gastrointestinaltract. Neurogastroenterol Motil 19(1 Suppl, 2007):1-19; ANDREWS P L,Sanger G J. Abdominal vagal afferent neurones: an important target forthe treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2(6,2002):650-656].

Preganglionic parasympathetic efferent nerve fibers to the stomach arecarried almost entirely in the vagus nerves that arise from the dorsalmotor nucleus (See FIG. 1). Postganglionic neurons of the gastricparasympathetic system are located mainly in the myenteric andsubmucosal plexuses of the enteric nervous system, with theparasympathetic ganglia shown in FIG. 1 to be attached to the entericnervous system, within the wall of the gut. Thus, on reaching theenteric plexuses, individual vagal axons ramify extensively and widely,contacting large numbers of enteric neurons [POWLEY T L. Vagal input tothe enteric nervous system. Gut 47 (2000) Suppl 4:iv30-2]. Stimulationof these parasympathetic nerve fibers generally causes an increase inactivity of the entire enteric nervous system, which in turn enhancesactivity of most gastric functions, owing to the fact that theparasympathetic neurotransmitter acetylcholine generally excites gastricactivity. However, the parasympathetic efferent fibers may also inhibitactivity as follows. Vagal preganglionic efferents to the stomach thatexcite or inhibit smooth muscle contraction form two pathways. First,there is an excitatory pathway with cholinergic preganglionic neuronsfrom the rostral dorsal motor nucleus and cholinergic postganglionicneurons in the enteric ganglia (transmitters Ach or Substance P).Second, there is an inhibitory pathway with cholinergic preganglionicneurons from the caudal dorsal motor nucleus and nitrergicpostganglionic neurons in the enteric ganglia (transmitters nitricoxide, VIP, or ATP). These excitatory and inhibitory pathways alsoregulate the activity of interstitial cells of Cajal, which in turnmodulate the contraction of smooth muscle cells. Thus, vagal efferentsmay either contract or relax gastric smooth muscle, depending on theselective stimulation of particular excitatory or inhibitory fibers thatoriginate in particular locations of the dorsal motor nucleus [CHANG HY, Mashimo H, Goyal R K. Musings on the wanderer: what's new in ourunderstanding of vago-vagal reflex? I V. Current concepts of vagalefferent projections to the gut. Am J Physiol Gastrointest Liver Physiol284(3, 2003):G357-G366; PAGANI F D, Norman W P, Kasbekar D K, Gillis RA. Localization of sites within dorsal motor nucleus of vagus thataffect gastric motility. Am J Physiol 249(1 Pt 1, 1985):G73-G84].

So-called vago-vagal reflex circuits cause smooth muscle of the stomachto contract or relax in response to afferent sensory signals that aresent from the stomach and other portions of the gastrointestinal tract.The circuits are comprised of sensory afferent fibers whose terminalsimpinge on nucleus tractus solitarius (NTS) neurons, which project todorsal motor nucleus (DMV) cells, which in turn provide thepreganglionic efferent fibers controlling excitatory and inhibitorypostganglionic cells. The strategic location outside the blood-brainbarrier of vago-vagal circuits, including the area postrema, makes themaccessible to circulating hormones, cytokines, and chemokines that candramatically alter vago-vagal reflex responsiveness [TRAVAGLI R A,Hermann G E, Browning K N, Rogers R C. Musings on the wanderer: what'snew in our understanding of vago-vagal reflexes? III. Activity-dependentplasticity in vago-vagal reflexes controlling the stomach. Am J PhysiolGastrointest Liver Physiol 284(2, 2003):G180-G187; Richard A. GILLIS,John A. Quest, Francis D. Pagani, Wesley P. Norman. Control centers inthe central nervous system for regulating gastrointestinal motility.Compr Physiol 2011, Supplement 16: Handbook of Physiology, TheGastrointestinal System, Motility and Circulation: 621-683 (firstpublished 1989); TRAVAGLI R A, Hermann G E, Browning K N, Rogers R C.Brainstem circuits regulating gastric function. Annu Rev Physiol 68(2006):279-305; BROWNING K N, Travagli R A. Plasticity of vagalbrainstem circuits in the control of gastric function.Neurogastroenterol Motil 22(11, 2010)1154-63].

Vagal activation during meals starts when thought, sight, smell andtaste of food stimulate gastrointestinal secretion, motility and hormonerelease. Subsequently, vago-vagal reflexes, elicited by the distensionof the esophagus and the stomach, induce antral contractions andreceptive and adaptive relaxation of the proximal stomach, ensuringgastric accommodation to the meal. The motor responses of the proximalstomach are then mediated by complex, partly antagonistic vagalpathways. There may be three possible mechanisms of gastric dysfunctionin patients with functional dyspepsia, all of which may involve thevagus nerve: (i) delayed gastric emptying as in gastroparesis, (ii)impaired gastric accommodation of food intake, and (iii)hypersensitivity to gastric distention.

Sympathetic gastric fibers originate in celiac sympathetic ganglia andterminate mainly on the enteric plexuses, but a few nerves terminate inthe mucosa itself. Messenger molecules mediate input to the ganglia andmodulate sympathetic efferent output, for example, the hormone leptinand carbon monoxide, which is synthesized by heme oxygenase 2. Thesympathetic fibers tend to course beside blood vessels (BV in FIG. 1).Their stimulation generally inhibits activity of the stomach, primarilyby inhibiting action in the enteric plexuses. Sympapthetic efferentsinnervate both precapillary and postcapillary blood vessels in thestomach and modulate gastric blood flow, in conjunction with the entericnerves. Sympathetic regulation of motility primarily involves inhibitorypresynaptic modulation of vagal cholinergic input to postganglionicneurons in the enteric plexus [O LUNDGREN. Sympathetic input into theenteric nervous system. Gut 47(Suppl IV, 2000):iv33-iv35; LOMAX A E,Sharkey K A, Furness J B. The participation of the sympatheticinnervation of the gastrointestinal tract in disease states.Neurogastroenterol Motil 22(1, 2010):7-18].

Stomach muscle contractions occur rhythmically, due to so-called “slowwaves” of smooth muscle membrane potential. The slow waves are caused byinteractions among the gastric smooth muscle cells (SM in FIG. 1) andnetworks of interstitial cells of Cajal (ICC, see FIG. 1). Theseinterstitial cells undergo spontaneous cyclic changes in membranepotential and act as electrical pacemakers for the gastric smooth musclecells. The slow waves may result in muscle contraction in the stomach,and they may also produce spike potentials that in turn cause musclecontraction. Electrical signals that initiate muscle contractions travelfrom one muscle fiber to adjacent muscle fibers via gap junctions[MOSTAFA R M, Moustafa Y M, Hamdy H. Interstitial cells of Cajal, theMaestro in health and disease. World J Gastroenterol 16(26,2010):3239-3248].

There are multiple subtypes of ICC cells, including those that formnetworks in the myenteric plexus (ICC-MY cells) and those inintramuscular networks (ICC-IM cells). Both ICC-MY and ICC-IM are likelyto serve a major role in slow wave generation and propagation. Asdescribed below, the ICC-IM are particularly relevant to the presentinvention because vagal gastrointestinal mechanoreceptors at the smoothmuscle endings of vagus afferent nerves, known as intramuscular arrays(IMA, see FIG. 1), form substantial contacts with interstitial cells ofCajal of the intramuscular type (ICC-IM) [Dirk F .van HELDEN, Derek R.Layer, John Holdsworth and Mohammad S. Imtiaz. The generation andpropagation of gastric slow waves. Proceedings of the AustralianPhysiological Society 40 (2009): 109-120; POWLEY T L, Wang X Y, Fox E A,Phillips R J, Liu L W, Huizing a J D. Ultrastructural evidence forcommunication between intramuscular vagal mechanoreceptors andinterstitial cells of Cajal in the rat fundus. Neurogastroenterol Motil20(1, 2008):69-79].

FIG. 1 shows smooth muscle cells (SM) in contact with a network ofinterstitial cells of Cajal (ICC network), which in turn lies adjacentto motor neurons of the enteric nervous system. These three structuresconstitute a gastrointestinal neuromuscular junction, in which entericmotor neurons stimulate or inhibit contraction of the smooth musclecells, with the ICC serving as an intermediary. When action potentialsinvade varicosities of the enteric motor neurons, stored transmittersare released (ATP and VIP for inhibitory neurons and ACh and SP forexcitatory neurons), and enzymes responsible for de novo transmittersare activated. In particular, in inhibitory enteric motor neurons, NO ismade by Ca-dependent activation of nitric oxide synthase—NOS). The closeapposition between varicose nerve terminals and ICC facilitate rapiddiffusion to receptors expressed by ICC. ICC are electrically coupled tosmooth muscle via gap junctions, and electrical responses elicited inICC are conveyed to smooth muscle cells via electrical conduction. Inthe smooth muscle cells, excitatory depolarization responses enhanceexcitability and increase Ca influx, or inhibitory hyperpolarizationresponses reduce excitability and block contraction [Alan J. BURNS, AlanE. J. Lomax, Shigeko Torihashi, Kenton M. Sanders, and Sean M. Ward.Interstitial cells of Cajal mediate inhibitory neurotransmission in thestomach. Proc. Natl. Acad. Sci. USA 93 (1996):12008-12013; S WARD.Interstitial cells of Cajal in enteric neurotransmission. Gut 47(Suppl4, 2000): iv40-iv43; WARD S M, Sanders K M. Interstitial cells of Cajal:primary targets of enteric motor innervation. The Anatomical Record262(1, 2001):125-135; Satoshi IINO and Kazuhide Horiguchi. InterstitialCells of Cajal Are Involved in Neurotransmission in the GastrointestinalTract. Acta Histochem Cytochem 39(6, 2006): 145-153].

The neurotransmitter receptors are also expressed by smooth musclecells, and they may also be used without intermediation by the ICC. Thatis to say, neuromuscular activation or inhibition may also be betweenenteric motor neurons and smooth muscle cells alone [HUIZINGA J D, Liu LW, Fitzpatrick A, White E, Gill S, Wang X Y, Zarate N, Krebs L, Choi C,Starret T, Dixit D, Ye J. Deficiency of intramuscular ICC increasesfundic muscle excitability but does not impede nitrergic innervation. AmJ Physiol Gastrointest Liver Physiol 294(2, 2008): G589-G594; GOYAL R K,Chaudhury A. Mounting evidence against the role of ICC inneurotransmission to smooth muscle in the gut. Am J Physiol GastrointestLiver Physiol 298(1, 2010):G10-G3]. However, if mature and functionalICC are not present in the neuromuscular junction of stomach muscle,neuromuscular transmission may be suboptimal or dysfunctional, leadingto gastric mobility problems.

In fact, loss of ICC is the single most common pathophysiologicalfeature found in patients with gastroparesis, and it is commonlyobserved in gastroparetic animal models as well [GROVER M, Farrugia G,Lurken M S, et al. Cellular changes in diabetic and idiopathicgastroparesis. Gastroenterology 140(5, 2011):1575-1585; Harsha VITTAL,Gianrico Farrugia, Guillermo Gomez and Pankaj J. Pasricha. Mechanisms ofDisease: the pathological basis of gastroparesis—a review ofexperimental and clinical studies. Nat Clin Pract Gastroenterol Hepatol4(6, 2007):336-346; ZARATE N, Mearin F, Wang X Y, Hewlett B, Huizing a JD, Malagelada J R. Severe idiopathic gastroparesis due to neuronal andinterstitial cells of Cajal degeneration: pathological findings andmanagement. Gut 52(7, 2003):966-70; BATTAGLIA E, Bassotti G, Bellone G,Dughera L, Serra A M, Chiusa L, Repici A, Mioli P, Emanuelli G. Loss ofinterstitial cells of Cajal network in severe idiopathic gastroparesis.World J Gastroenterol 12(38, 2006):6172-6177; FORSTER J, Damjanov I, LinZ, Sarosiek I, Wetzel P, McCallum R W. Absence of the interstitial cellsof Cajal in patients with gastroparesis and correlation with clinicalfindings. J Gastrointest Surg 9(1, 2005):102-108; LIN Z, Sarosiek I,Forster J, Damjanov I, Hou Q, McCallum R W. Association of the status ofinterstitial cells of Cajal and electrogastrogram parameters, gastricemptying and symptoms in patients with gastroparesis. NeurogastroenterolMotil 22(1, 2010):56-61; WANG X Y, Huizing a J D, Diamond J, Liu L W.Loss of intramuscular and submuscular interstitial cells of Cajal andassociated enteric nerves is related to decreased gastric emptying instreptozotocin-induced diabetes. Neurogastroenterol Motil 21(10, 2009):1095-e92; ORDOG T, Takayama I, Cheung W K, Ward S M, Sanders K M.Remodeling of networks of interstitial cells of Cajal in a murine modelof diabetic gastroparesis. Diabetes 49(10, 2010)1731-1739].

ICC injury may be due to a deficiency of growth factors necessary fornormal ICC survival. For example, in diabetes, defective insulin andinsulin-like growth factor I (IGF-I) pathways are thought to lead to ICCdepletion. ICC injury seems to have gradations: structural injury to ICCwithout loss of ICC, followed by a reduction in the density of thenetworks of ICC with preservation of some function, followed by moresevere loss up to complete loss of function. When the ICC are lost, thecells may not actually die, but may instead dedifferentiate into cellshaving smooth muscle and fibroblast features. The process may also bereversible, wherein such un- or de-differentiated cells become matureICC after the appropriate trophic factors are supplied [HUIZINGA J D,White E J. Progenitor cells of interstitial cells of Cajal: on the roadto tissue repair. Gastroenterology 134(4, 2008):1252-1254; MEI F, Yu B,Ma H, Zhang H J, Zhou D S. Interstitial cells of Cajal could regenerateand restore their normal distribution after disrupted by intestinaltransection and anastomosis in the adult guinea pigs. Virchows Arch449(3, 2006):348-57; LORINCZ A, Redelman D, Horváth V J, Bardsley M R,Chen H, Ordög T. Progenitors of interstitial cells of cajal in thepostnatal murine stomach. Gastroenterology 134(4, 2008)1083-1093].

Therefore, it is one objective of the present invention to providerequisite trophic factors to gastric ICC cells and their progenitors,through electrical stimulation of the vagus nerve. Certain ICC are knownto require functionally intact innervation by the vagus nerve, otherwisethe ICC will be damaged or lost. Such ICC are found in association withintramuscular arrays (IMA, see FIG. 1). The IMA are vagalmechanoreceptors, consisting of arrays of parallel telodendria runningin close proximity to one another and to muscle fibers. They sendafferent mechanical information via vagal nerves, apparently servingmuch the same type of function as skeletal muscle spindles. IMAs lie inclose association not only with ICCs, but also with other afferent andefferent axons, presumed to be enteric neurons, that conceivably usetransduced signals from the IMAs in the performance of feedback loopsthat tune the mechanical responses to IMAs dynamically (see FIG. 1)[POWLEY T L, Phillips R J. Vagal intramuscular array afferents formcomplexes with interstitial cells of Cajal in gastrointestinal smoothmuscle: analogues of muscle spindle organs? Neuroscience 186(2011):188-200; POWLEY T L, Wang X Y, Fox E A, Phillips R J, Liu L W,Huizing a J D. Ultrastructural evidence for communication betweenintramuscular vagal mechanoreceptors and interstitial cells of Cajal inthe rat fundus. Neurogastroenterol Motil 20(1, 2008):69-79].

When vagal afferents are deliberately damaged by injections into thenodose ganglion, degeneration of ICCs associated with IMAs occursshortly thereafter [HUIZINGA J D, Reed D E, Berezin I, Wang X Y, ValdezD T, Liu L W, Diamant N E. Survival dependency of intramuscular ICC onvagal afferent nerves in the cat esophagus. Am J Physiol Regul lntegrComp Physiol 294(2, 2008):R302-R310]. This indicates that the vagusafferent is not only serving as an afferent transmitter of informationabout the mechanical state in the vicinity of the IMA, but is alsoresponsible in part for maintaining the functional and structuralintegrity of ICCs. That is to say, the vagal afferent nerve appears tobe providing factors necessary for the maintenance of ICCs. In thatregard, it is well established that gastrointestinal vagal afferentssubserve an efferent role by release of neurotransmitters or otherfactors from their varicose nerve terminals [RAYBOULD H E. The future ofGI and liver research: editorial perspectives. IV. Visceral afferents:an update. Am J Physiol Gastrointest Liver Physiol 284(6,2003):G880-G882]. Even some putative gastric afferents derived fromdorsal root ganglia behave as though they were efferent nerves [HOLZERP, Maggi C A. Dissociation of dorsal root ganglion neurons into afferentand efferent-like neurons. Neuroscience 86(2, 1998):389-398].

Interaction between nerves and muscles can be considered at two levels:short-term interaction (or neurotransmission) that takes seconds orless, and long-term interaction that concerns development and takeslonger, sometimes days. The line between these is not distinct and thereare semantic problems in defining neurotransmitters, neuromodulators,neurohormones, second messengers and trophic factors. So, for want of abetter term, the factors that are provided by the vagus afferent topromote ICC maintenance are labeled in FIG. 1 as “trophic factor”. Theidentity of the trophic factor(s) at the IMA is not known, although StemCell Factor (also known as SCF, kit-ligand, KL, or steel factor) has awell known role in the maturation and maintenance of ICC, and the vagusafferent could either provide SCF itself, or produce trophic effects onadjacent smooth muscle cells or neighboring enteric neurons, causingthem to provide sufficient quantities of SCF to the ICC (or other suchtrophic factors, e.g., involving nNOS and nitric oxide) [LORINCZ A,Redelman D, Horváth V J, Bardsley M R, Chen H, Ordög T. Progenitors ofinterstitial cells of cajal in the postnatal murine stomach.Gastroenterology 134(4, 2008):1083-1093; TORIHASH I S, Yoshida H,Nishikawa S, Kunisada T, Sanders K M. Enteric neurons express Steelfactor-lacZ transgene in the murine gastrointestinal tract. Brain Res738(2, 1996):323-328].

In the gastroparetic patient, the ICC may have become damaged by avariety of mechanisms, and the corresponding IMA therefore will not betransmitting normal vagal afferent signals. In particular, the smoothmuscle in the absence of ICC might have increased excitability, suchthat vagal afferent signals from the IMA are abnormal [HUIZINGA J D, LiuL W, Fitzpatrick A, White E, Gill S, Wang X Y, Zarate N, Krebs L, ChoiC, Starret T, Dixit D, Ye J. Deficiency of intramuscular ICC increasesfundic muscle excitability but does not impede nitrergic innervation. AmJ Physiol Gastrointest Liver Physiol 294(2, 2008): G589-G594]. Anobjective of the invention is to electrically stimulate the vagusafferent nerve so as to imitate signals that would normally have beentransmitted by the vagal afferents, such that the vagus nerve willrespond by providing to the damaged ICC what would have been the normaltrophic factors. This will thereby reverse ICC damage, and as aconsequence improve gastric motility. Thus, one aspect of the inventionis to electrical stimulate the vagal afferents in such a way as tosignal to cell nuclei within the nodose ganglion that the ICC-associatedmechanoreceptors are active normally (even though they are not) andrespond accordingly to produce and transport the normal trophic factors.To the extent that the vagal afferent signals without externally appliedelectrical stimulation are sensed as being nociceptive, imposition ofthe externally applied normal signal will also relieve unpleasantsensations.

Such stimulation of the afferent vagus nerve over a short period of timewill not necessarily have a long-lasting therapeutic effect, even takinginto account the time needed for the resulting trophic factors toreverse ICC damage. Instead, according to the present invention,restored gastric mobility may occur more or less abruptly after aprotocol of vagus nerve stimulation treatment over a period of days orweeks, for the following reasons. Individual interstitial cells of Cajalof both the ICC-IM and ICC-MY types are intrinsically rhythmic and actas pacemakers for waves of contraction [Dirk F. van HELDEN, Derek R.Layer, John Holdsworth and Mohammad S. Imtiaz. The generation andpropagation of gastric slow waves. Proceedings of the AustralianPhysiological Society 40 (2009): 109-120]. The cells' rhythms are notindependent of one another, however, because they are mechanically andelectrically coupled with one another, at a minimum through entericnerves and intervening smooth muscle. Therefore the cells within anetwork of interstitial cells of Cajal may be regarded as a set ofsemi-autonomous oscillators, coupled to one another.

Local mechanical oscillations of the stomach would damp themselves outthrough friction, were they not sustained by a source of metabolicenergy, i.e., the equation describing the oscillation will generally benon-conservative. Furthermore, because the velocities of displacement ofmuscle segments relative to their average or resting position aregenerally not linearly proportional to the displacements themselves,because the period of oscillation may be a function of the oscillationamplitude rather than a simple constant, and because the tension andcompression that segments exert upon one another are likewise generallymore complicated than a simple spring constant, then equations thatcharacterize the oscillators and their interactions must generally benon-linear. The properties of such non-linear oscillators are currentlyunderstood through the analysis of non-linear differential equationprototypes, such as Van der Pol, FitzHugh-Nagumo, Morris-Lecar,Ellias-Grossberg, and Stuart-Landau equations.

Although the detailed oscillations described by such prototypicalequations are dependent on the detailed form of the equations, thequalitative behaviors of such non-linear coupled oscillator equationsmay often be understood independently of the particular form of thenon-linear equation. For example, it is well understood in general thatnon-linear oscillators, including a set of coupled non-linearoscillators, may exhibit qualitatively different behaviors when theparameters of their equations lie within certain bounds. When graphs aredrawn showing the value of one parameter on one axis, and the value ofanother parameter on another axis, regions of this parameter space maybe circumscribed to show what sets of parameter values correspond toeach type of qualitatively different dynamics, i.e, a phase diagram.Examples of such phase diagrams, which are given by MATTHEWS andcolleagues, circumscribe different regions of phase space havingqualitatively different dynamics [Paul C. MATTHEWS and Steven H.Strogatz. Phase diagram for the collective behavior of limit-cycleoscillators. Phys. Rev. Lett. 65 (1990): 1701-1704; Paul C. MATTHEWS andSteven H. Strogatz. Phase diagram for the collective behavior oflimit-cycle oscillators. Phys. Rev. Lett. 65 (1990): 1701-1704; Paul C.MATTHEWS, Renato E. Mirollo, and Steven H. Strogatz. Dynamics of a largesystem of coupled nonlinear oscillators. Physica D: Nonlinear Phenomena52 (2-3, 1991): 293-331]. According to the present invention, a patientwith gastroparesis has a stomach with ICC that are trapped in a regionof phase space in which gastric emptying dynamics is abnormal. Anobjective of the invention is to move the system of coupled non-linearoscillators (ICC network) into a region of phase space corresponding tomore nearly normal gastric emptying. When doing so, there may be anabrupt change in physiological dynamics, as the system passes theboundary from one qualitatively different dynamical region in phasespace to another.

When one or more of the parameters of the set of coupled nonlinearoscillators may be varied under external influences to producequalitative changes of phase in the system, the parameter is said to bean order parameter. When a network of interstitial cells of Cajal arerepresented mathematically as nonlinear oscillators that are coupled toone another, an order parameter for the system may be, for example, thevolume of food in the stomach. Another order parameter can be related tothe magnitude and duration of vagus nerve stimulation. For example, letthe accumulated “Vagus Nerve stimulation” with a particular stimulationwaveform be denoted as S(t), which may for illustration purposes berepresented as one that increases at a rate proportional to thestimulation voltage V and decays with a time constant τ_(P), such thatafter prolonged stimulation, the accumulated stimulation effectivenesswill saturate at a value equal to the product of V and τ_(P). Thus, ifT_(P) is the duration of a stimulus pulse, then for time t<T_(P),S(t)=Vτ_(P)[1−exp(−t/τ_(P))]+S₀ exp(−t/τ_(P)), and for t>T_(P),S(t)=S(T_(P))exp(−[t−T_(P)]/τ_(P)) where the time t is measured from thestart of a pulse, and S₀ is the value of S when t=0. Then, as stimuli tothe vagus nerve are applied, the value of S will change to move thesystem within phase space. It may therefore be possible for the systemto switch from one dynamical phase to another, even if the stomach had aconstant volume (or other such order parameter was constant). Therefore,treatment over an extended period of time by vagus nerve stimulation maybe required in order to achieve the objective of changing thequalitative dynamics of the network of interstitial cells of Cajal, bymoving the system into a more normal region of phase space. This mayinvolve adaptive changes in the above-mentioned vago-vagal reflexes,which also couple interstitial cells of Cajal to one another.

A disclosure similar to the foregoing was made by Applicants inconnection with the treatment bladder smooth muscle motility disorders,in commonly assigned co-pending patent application US20120101326,entitled Non-invasive electrical and magnetic nerve stimulators used totreat overactive bladder and urinary incontinence, to SIMON et al.,which is hereby incorporated by reference. It is understood thatnonlinear coupled oscillator equations describing gastric emptying(rather than bladder emptying) may be constructed by adapting previouslydescribed models of stomach dynamics [DU P, O'Grady G, Gibbons S J,Yassi R, Lees-Green R, Farrugia G, Cheng L K, Pullan A J.Tissue-specific mathematical models of slow wave entrainment inwild-type and 5-HT(2B) knockout mice with altered interstitial cells ofCajal networks. Biophys J 98(9, 2010):1772-1781; LEES-GREEN R, Du P,O'Grady G, Beyder A, Farrugia G, Pullan A J. Biophysically basedmodeling of the interstitial cells of cajal: current status and futureperspectives. Front Physiol 2 (2011):29, pp. 1-19].

Gastroparesis and functional dyspepsia are accompanied by abnormalinteroception and visceral hypersensitivity. Many neural circuits thatare involved in interoception are located in higher regions of thecentral nervous system, and a further objective of the invention is toelectrically stimulate the vagus nerve in such a way as to modulate theactivity of those neural circuits. They are also shown in of FIG. 1 anddescribed in paragraphs that follow [CRAIG A D. How do you feel?Interoception: the sense of the physiological condition of the body. NatRev Neurosci 3(8, 2002):655-666; BIELEFELDT K, Christianson J A, Davis BM. Basic and clinical aspects of visceral sensation: transmission in theCNS. Neurogastroenterol Motil 17(4, 2005):488-499; MAYER E A, Naliboff BD, Craig A D. Neuroimaging of the brain-gut axis: from basicunderstanding to treatment of functional GI disorders. Gastroenterology131(6, 2006)1925-1942].

Sensations of gastrointestinal pain and unpleasantness (e.g. nausea andearly satiety) arise from signals sent by parasympathetic andsympathetic afferent nerves. The latter are considered to be the primaryculprit for pain, but as described below, parasympathetic afferents alsocontribute [M KOLLARIK, F Ru and M Brozmanova. Vagal afferent nerveswith the properties of nociceptors. Auton Neurosci 153(1-2, 2010): 12,pp. 1-20]. Among afferents whose cell bodies are found in the dorsalroot ganglia, the ones having type B cell bodies are most significant(see FIG. 1). They terminate in lamina I of the spinal and trigeminaldorsal horns, which for stomach afferents correspond largely to spinallevels T6-T9. Other afferent nerves that terminate in the deep dorsalhorn provide signals related to mechanoreceptive, proprioceptive andnociceptive activity (not shown), but in general they are notresponsible for unpleasant sensations.

Lamina I neurons project to many locations. First, they project to thesympathetic regions in the intermediomedial and intermediolateral cellcolumns of the thoracolumbar cord, where the sympathetic preganglioniccells of the autonomic nervous system originate (See FIG. 1). Forgastric sympathetic nerves, the preganglionic nerves project to theceliac ganglia, from which the postgangionic efferent nerves innervatingthe stomach wall and gastric blood vessels arise.

Second, in the medulla, lamina I neurons project to the A1catecholaminergic cell groups of the ventrolateral medulla and then tosites in the rostral ventrolateral medulla (RVLM) which isinterconnected with the sympathetic neurons that project to spinallevels. Only a limited number of discrete regions within the supraspinalcentral nervous system project to sympathetic preganglionic neurons inthe intermediolateral column (see FIG. 1). The most important of theseregions are the rostral ventral lateral medulla (RVLM), the rostralventromedial medulla (RVMM), the midline raphe, the paraventricularnucleus (PVN) of the hypothalamus, the medullocervical caudal pressorarea (mCPA), and the A5 cell group of the pons. The first four of theseconnections to the intermediolateral nucleus are shown in FIG. 1 [STRACKA M, Sawyer W B, Hughes J H, Platt K B, Loewy A D. A general pattern ofCNS innervation of the sympathetic outflow demonstrated by transneuronalpseudorabies viral infections. Brain Res. 491(1, 1989): 156-162].

The rostral ventral lateral medulla (RVLM) is the primary regulator ofthe sympathetic nervous system, sending excitatory fibers(glutamatergic) to the sympathetic preganglionic neurons located in theintermediolateral nucleus of the spinal cord. Vagal afferents synapse inthe NTS, and their projections reach the RVLM via the caudalventrolateral medulla. However, resting sympathetic tone also comes fromsources above the pons, from hypothalamic nuclei, various hindbrain andmidbrain structures, as well as the forebrain and cerebellum, whichsynapse in the RVLM. Only the hypothalamic projection to the RVLM isshown in FIG. 1.

The RVLM shares its role as a primary regulator of the sympatheticnervous system with the rostral ventromedial medulla (RVMM) andmedullary raphe. Differences in function between the RVLM versusRVMM/medullary raphe have been elucidated for cardiovascular control,but are not well characterized for gastrointestinal control.Differential control of the RVLM by the hypothalamus may also occur viacirculating hormones such as vasopressin. The RVMM contains at leastthree populations of nitric oxide synthase neurons that send axons toinnervate functionally similar sites in the NTS and nucleus ambiguus.Circuits connecting the RVMM and RVLM may be secondary, via the NTS andhypothalamus.

In the medulla, lamina I neurons also project another site, namely, tothe A2 cell group of the nucleus of the solitary tract, which alsoreceives direct parasympathetic (vagal and glossopharyngeal) afferentinput. As indicated above, the nucleus of the solitary tract projects tomany locations, including the parabrachial nucleus. In the pons andmesencephalon, lamina I neurons project to the periaqueductal grey(PAG), the main homeostatic brainstem motor site, and to theparabrachial nucleus. Sympathetic and parasympathetic afferent activityis integrated in the parabrachial nucleus. It in turn projects to theinsular cortex by way of the ventromedial thalamic nucleus (VMb, alsoknown as VPMpc). A direct projection from lamina I to the ventromedialnucleus (VMpo), and a direct projection from the nucleus tractussolitarius to the VMb, provide a rostrocaudally contiguous column thatrepresents all contralateral homeostatic afferent input. They projecttopographically to the mid/posterior dorsal insula (See FIG. 1).

In humans, this cortical image is re-represented in the anterior insulaon the same side of the brain. The parasympathetic activity isre-represented in the left (dominant) hemisphere, whereas thesympathetic activity is re-represented in the right (non-dominant)hemisphere. These re-representations provide the foundation for asubjective evaluation of interoceptive state, which is forwarded to theorbitofrontal cortex (See FIG. 1).

The right anterior insula is associated with subjective awareness ofhomeostatic emotions (e.g., visceral and somatic pain, temperature,sexual arousal, hunger, and thirst) as well as all emotions (e.g.,anger, fear, disgust, sadness, happiness, trust, love, empathy, socialexclusion). This region is intimately interconnected with the anteriorcingulate cortex (ACC). The unpleasantness of pain is directlycorrelated with ACC activation. The anterior cingulate cortex and insulaare both strongly interconnected with the orbitofrontal cortex,amygdala, hypothalamus, and brainstem homeostatic regions, of which onlya few connections are shown in FIG. 1.

Visceral pain and hypersensitivity is a characteristic feature inpatients with FGID such as functional dyspepsia. In view of FIG. 1, thepathophysiological basis of hypersensitivity may be a combination ofsensitized visceral afferent pathways (enteric, parasympathetic,sympathetic), alterations in cortical processing of visceral afferentinputs, and changes in descending modulatory inputs from the brainstemto the spinal cord, and to enteric neurones via the vagus nerve. Therelative contributions of particular ascending and descending pathwaysare likely to vary from patient to patient [ANAND P, Aziz Q, Willert R,van Oudenhove L. Peripheral and central mechanisms of visceralsensitization in man. Neurogastroenterol Motil 19(1 Suppl, 2007):29-46;Clive H WILDER-SMITH. The balancing act: endogenous modulation of painin functional gastrointestinal disorders. Gut 60 (2011)1589-1599].

Methods of the present invention comprise modulation of two targetregions using vagus nerve stimulation to reduce visceral pain,unpleasantness, and hypersensitivity. A first method targets the frontend of the interoceptive pathways shown in FIG. 1 (nucleus tractussolitarius, area postrema, and dorsal motor nucleus). A second methodtargets the distal end of the interoceptive pathways (anterior insulaand anterior cingulate cortex).

According to the first method, electrical stimulation of A and B fibersalone of a vagus nerve causes increased inhibitory neurotransmitters inthe brainstem, which in turn inhibits signals sent to the parabrachialnucleus, VMb and VMpo. The stimulation uses special devices and aspecial waveform (described below), which minimize effects involving Cfibers that might produce unwanted side-effects. The electricalstimulation first affects the dorsal vagal complex, which is the majortermination site of vagal afferent nerve fibers. The dorsal vagalcomplex consists of the area postrema (AP), the nucleus of the solitarytract (NTS) and the dorsal motor nucleus of the vagus. The AP projectsto the NTS and dorsal motor nucleus of the vagus bilaterally. It alsoprojects bilaterally to the parabrachial nucleus and receives directafferent input from the vagus nerve. Thus, the area postrema is in aunique position to receive and modulate ascending interoceptiveinformation and to influence autonomic outflow [PRICE C J, Hoyda T D,Ferguson A V. The area postrema: a brain monitor and integrator ofsystemic autonomic state. Neuroscientist 14(2, 2008)182-194].

The area postrema (AP) is well known as the medullary structure in thebrain that controls vomiting, but it may play a more general role inmediating introceptive sensations, comprising not only vomiting, butalso such sensations as postprandial fullness, bloating, pain, andnausea. It is able to play this role because of its ability to sensecirculating hormones and other soluble physiologically active factors,such as toxins. It is heavily vascularized, and by virtue of its lack oftight junctions between endothelial cells and the presence offenestrated capillaries, peptide and other physiological signals bornein the blood have direct access to its neurons that project to the NTS,dorsal motor nucleus and parabrachial nucleus. This includes hormonesthat are secreted before and after ingesting a meal, such as gherlin andcholecystokinin. An addition, the AP receives direct afferent input fromthe vagus nerve, including afferents from the stomach.

Excitatory nerves within the dorsal vagal complex generally useglutamate as their neurotransmitter. To inhibit neurotransmission withinthe dorsal vagal complex, the present invention makes use of thebidirectional connections that the NTS has with structures that produceinhibitory neurotransmitters, or it makes use of connections that theNTS has with the hypothalamus, which in turn projects to structures thatproduce inhibitory neurotransmitters. The inhibition is produced as theresult of the stimulation waveforms that are described below. Thus,acting in opposition to glutamate-mediated (and possibly substance P)activation of the AP and dorsal motor nucleus by the NTS are GABA,and/or serotonin, and/or norepinephrine from the periaqueductal gray,raphe nucei, and locus coeruleus, respectively. FIG. 1 shows how thoseexcitatory and inhibitory influences combine to modulate the output ofthe dorsal motor nucleus. Similar influences combine within the NTSitself, and the combined inhibitory influences on the NTS and dorsalmotor nucleus produce an inhibitory effect on the AP through theirefferent projections to the AP. The combined inhibitory effects on theNTS and AP thereby inhibit the signals projected to the parabrachialnucleus, VMb and VMpo, thus inhibiting unpleasant interoceptivesensations.

The activation of inhibitory circuits in the periaqueductal gray, raphenucei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1 [PUDOVKINA O L, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol 7 (2002);445(1-2):37-42; REICHLING D B, Basbaum A I. Collateralization ofperiaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience 42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in the functionof the nucleus raphe magnus and in the interaction of this nucleus withthe periaqueductal gray. Brain Res 252(2, 1982):299-307].

Projections to and from the locus ceruleus are particularly significantin the present invention because they are also used in the second methodthat is described below. The vagus nerve transmits information to thelocus ceruleus via the nucleus tractus solitarius (NTS), which has adirect projection to the dendritic region of the locus ceruleus. Otherafferents to, and efferents from, the locus ceruleus are described bySARA et al, SAMUELS et al, and ASTON-JONES—SARA S J, Bouret S. Orientingand Reorienting: The Locus Coeruleus Mediates Cognition through Arousal.Neuron 76(1, 2012):130-41; SAMUELS E R, Szabadi E. Functionalneuroanatomy of the noradrenergic locus coeruleus: its roles in theregulation of arousal and autonomic function part I: principles offunctional organisation. Curr Neuropharmacol 6(3):235-53; SAMUELS, E.R., and Szabadi, E. Functional neuroanatomy of the noradrenergic locuscoeruleus: its roles in the regulation of arousal and autonomic functionpart II: physiological and pharmacological manipulations andpathological alterations of locus coeruleus activity in humans. Curr.Neuropharmacol. 6 (2008), 254-285; Gary ASTON-JONES. Norepinephrine.Chapter 4 (pp. 47-57) in: Neuropsychopharmacology: The Fifth Generationof Progress (Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, CharlesNemeroff, eds.) Philadelphia: Lippincott Williams & Wilkins, 2002].

In addition to the NTS, the locus ceruleus receives input from thenucleus gigantocellularis and its neighboring nucleusparagigantocellularis, the prepositus hypoglossal nucleus, theparaventricular nucleus of the hypothalamus, Barrington's nucleus, thecentral nucleus of the amygdala, and prefrontal areas of the cortex.These same nuclei receive input from the NTS, such that stimulation ofthe vagus nerve may modulate the locus ceruleus via the NTS and asubsequent relay through these structures.

The locus ceruleus has widespread projections throughout the cortex[SAMUELS E R, Szabadi E. Functional neuroanatomy of the noradrenergiclocus coeruleus: its roles in the regulation of arousal and autonomicfunction part I: principles of functional organisation. CurrNeuropharmacol 6 (3):235-53]. It also projects to subcortical regions,notably the raphe nuclei, which release serotonin to the rest of thebrain. An increased dorsal raphe nucleus firing rate is thought to besecondary to an initial increased locus ceruleus firing rate from vagusnerve stimulation [Adrienne E. DORR and Guy Debonnelv. Effect of vagusnerve stimulation on serotonergic and noradrenergic transmission. JPharmacol Exp Ther 318(2, 2006):890-898; MANTA S, Dong J, Debonnel G,Blier P. Enhancement of the function of rat serotonin and norepinephrineneurons by sustained vagus nerve stimulation. J Psychiatry Neurosci34(4, 2009):272-80]. The locus ceruleus also has projections toautonomic nuclei, including the dorsal motor nucleus of the vagus, asshown in FIG. 1 [FUKUDA, A., Minami, T., Nabekura, J., Oomura, Y. Theeffects of noradrenaline on neurones in the rat dorsal motor nucleus ofthe vagus, in vitro. J. Physiol., 393 (1987): 213-231; MARTINEZ-PENA yValenzuela, I., Rogers, R. C., Hermann, G. E., Travagli, R. A. (2004)Norepinephrine effects on identified neurons of the rat dorsal motornucleus of the vagus. Am. J. Physiol. Gas-trointest. Liver Physiol.,286, G333-G339; TERHORST, G. J., Toes, G. J., Van Willigen, J. D. Locuscoeruleus projections to the dorsal motor vagus nucleus in the rat.Neuroscience, 45 (1991): 153-160].

In another embodiment of the invention, vagus nerve stimulation is usedto modulate the activity of particular neural networks known as restingstate networks, with the objective of reducing visceralhypersensitivity, pain, or other unpleasant sensations. A neural networkis accompanied by oscillations within the network. Low frequencyoscillations are likely associated with connectivity at the largestscale of the network, while higher frequencies are exhibited by smallersub-networks within the larger network, which may be modulated byactivity in the slower oscillating larger network. The default network,also called the default mode network (DMN), default state network, ortask-negative network, is one such network that is characterized bycoherent neuronal oscillations at a rate lower than 0.1 Hz. Other largescale networks also have this slow-wave property, as described below[BUCKNER R L, Andrews-Hanna J R, Schacter D L. The brain's defaultnetwork: anatomy, function, and relevance to disease. Ann N Y Acad Sci1124 (2008):1-38; PALVA J M, Palva S. Infra-slow fluctuations inelectrophysiological recordings, blood-oxygenation-level-dependentsignals, and psychophysical time series. Neuroimage 62(4,2012):2201-2211; STEYN-ROSS M L, Steyn-Ross D A, Sleigh J W, Wilson M T.A mechanism for ultra-slow oscillations in the cortical default network.Bull Math Biol 73(2, 2011):398-416].

The default mode network corresponds to task-independent introspection(e.g., daydreaming), or self-referential thought. When the DMN isactivated, the individual is ordinarily awake and alert, but the DMN mayalso be active during the early stages of sleep and during conscioussedation. During goal-oriented activity, the DMN is deactivated and oneor more of several other networks, so-called task-positive networks(TPN), are activated. DMN activity is attenuated rather thanextinguished during the transition between states, and is observed,albeit at lower levels, alongside task-specific activations. Strength ofthe DMN deactivation appears to be inversely related to the extent towhich the task is demanding. Thus, DMN has been described as atask-negative network, given the apparent antagonism between itsactivation and task performance. The posterior cingulate cortex (PCC)and adjacent precuneus and the medial prefrontal cortex (mPFC) are thetwo most clearly delineated regions within the DMN [RAICHLE M E, SnyderA Z. A default mode of brain function: a brief history of an evolvingidea. Neuroimage 37(4, 2007):1083-1090; BROYD S J, Demanuele C, DebenerS, Helps S K, James C J, Sonuga-Barke E J. Default-mode braindysfunction in mental disorders: a systematic review. Neurosci BiobehavRev 33(3, 2009):279-96; BUCKNER R L, Andrews-Hanna J R, Schacter D L.The brain's default network: anatomy, function, and relevance todisease. Ann N Y Acad Sci 1124 (2008):1-38; BUCKNER R L, Sepulcre J,Talukdar T, Krienen F M, Liu H, Hedden T, Andrews-Hanna J R, Sperling RA, Johnson K A. Cortical hubs revealed by intrinsic functionalconnectivity: mapping, assessment of stability, and relation toAlzheimer's disease. J Neurosci 29 (2009):1860-1873; GREICIUS M D,Krasnow B, Reiss A L, Menon V. Functional connectivity in the restingbrain: a network analysis of the default mode hypothesis. Proc Natl AcadSci USA 100 (2003): 253-258].

The term low frequency resting state networks (LFRSN or simply RSN) isused to describe both the task-positive and task-negative networks.Using independent component analysis (ICA) and related methods to assesscoherence of fMRI Blood Oxygenation Level Dependent Imaging (BOLD)signals in terms of temporal and spatial variation, as well asvariations between individuals, low frequency resting state networks inaddition to the DMN have been identified, corresponding to differenttasks or states of mind. They are related to their underlying anatomicalconnectivity and replay at rest the patterns of functional activationevoked by the behavioral tasks. That is to say, brain regions that arecommonly recruited during a task are anatomically connected and maintainin the resting state (in the absence of any stimulation) a significantdegree of temporal coherence in their spontaneous activity, which iswhat allows them to be identified at rest [SMITH S M, Fox P T, Miller KL, Glahn D C, Fox P M, et al. Correspondence of the brain's functionalarchitecture during activation and rest. Proc Natl Acad Sci USA 106(2009): 13040-13045].

Frequently reported resting state networks (RSNs), in addition to theDMN, include the sensorimotor RSN, the executive control RSN, up tothree visual RSNs, two lateralized fronto-parietal RSNs, the auditoryRSN and the temporo-parietal RSN. However, different investigators usedifferent methods to identify the low frequency resting state networks,so different numbers and somewhat different identities of RSNs arereported by different investigators [COLE D M, Smith S M, Beckmann C F.Advances and pitfalls in the analysis and interpretation ofresting-state FMRI data. Front Syst Neurosci 4 (2010):8, pp. 1-15].Examples of RSNs are described in publications cited by COLE and thefollowing: ROSAZZA C, Minati L. Resting-state brain networks: literaturereview and clinical applications. Neurol Sci 32(5, 2011):773-85; ZHANGD, Raichle M E. Disease and the brain's dark energy. Nat Rev Neurol 6(1,2010):15-28; DAMOISEAUX, J. S., Rombouts, S. A. R. B., Barkhof, F.,Scheltens, P., Stam, C. J., Smith, S. M., Beckmann, C. F. Consistentresting-state networks across healthy subjects. Proc. Natl. Acad. Sci.U.S.A. 103 (2006): 13848-13853 FOX M D, Snyder A Z, Vincent J L,Corbetta M, Van Essen D C, Raichle M E. The human brain is intrinsicallyorganized into dynamic, anticorrelated functional networks. Proc NatlAcad Sci USA 102 (2005):9673-9678; LI R, Wu X, Chen K, Fleisher A S,Reiman E M, Yao L. Alterations of Directional Connectivity amongResting-State Networks in Alzheimer Disease. AJNR Am J Neuroradiol. 2012Jul. 12. [Epub ahead of print, pp. 1-6].

For example, the dorsal attention network (DAN) and ventral attentionnetwork (VAN) are two networks responsible for attentional processing.The VAN is involved in involuntary actions and exhibits increasedactivity upon detection of salient targets, especially when they appearin unexpected locations (bottom-up activity, e.g. when an automobiledriver unexpectedly senses a hazard or unexpected situation). The DAN isinvolved in voluntary (top-down) orienting and increases activity afterpresentation of cues indicating where, when, or to what individualsshould direct their attention [FOX M D, Corbetta M, Snyder A Z, VincentJ L, Raichle M E. Spontaneous neuronal activity distinguishes humandorsal and ventral attention systems. Proc Natl Acad Sci USA 103(2006):10046-10051; WEN X, Yao L, Liu Y, Ding M. Causal interactions inattention networks predict behavioral performance. J Neurosci 32(4,2012):1284-1292]. The DAN is bilaterally centered in the intraparietalsulcus and the frontal eye field. The VAN is largely right lateralizedin the temporal-parietal junction and the ventral frontal cortex. Theattention systems (VAN and DAN) have been investigated long before theiridentification as resting state networks, and functions attributed tothe VAN have in the past been attributed to the locusceruleus/noradrenaline system [ASTON-JONES G, Cohen J D. An integrativetheory of locus coeruleus-norepinephrine function: adaptive gain andoptimal performance. Annu Rev Neurosci 28 (2005):403-50; BOURET S, SaraS J. Network reset: a simplified overarching theory of locus coeruleusnoradrenaline function. Trends Neurosci 28(11, 2005):574-82; SARA S J,Bouret S. Orienting and Reorienting: The Locus Coeruleus MediatesCognition through Arousal. Neuron 76(1, 2012):130-41; PETERSEN S E,Posner M I. The attention system of the human brain: 20 years after.Annu Rev Neurosci 35 (2012):73-89; BERRIDGE C W, Waterhouse B D. Thelocus coeruleus-noradrenergic system: modulation of behavioral state andstate-dependent cognitive processes. Brain Res Brain Res Rev 42(1,2003):33-84].

MENON and colleagues describe the anterior insula as being at the heartof the ventral attention system [ECKERT M A, Menon V, Walczak A,Ahlstrom J, Denslow S, Horwitz A, Dubno J R. At the heart of the ventralattention system: the right anterior insula. Hum Brain Mapp 30(8,2009):2530-2541; MENON V, Uddin L Q. Saliency, switching, attention andcontrol: a network model of insula function. Brain Struct Funct 214(5-6,2010):655-667]. SEELEY and colleagues used region-of-interest andindependent component analyses of resting-state fMRI data to demonstratethe existence of an independent brain network comprised of both theanterior insula and dorsal ACC, along with subcortical structuresincluding the amygdala, substantia nigra/ventral tegmental area, andthalamus. This network is distinct from the other well-characterizedlarge-scale brain networks, e.g. the default mode network (DMN) [SEELEYW W, Menon V, Schatzberg A F, Keller J, Glover G H, Kenna H, et al.Dissociable intrinsic connectivity networks for salience processing andexecutive control. J Neurosci 2007; 27(9):2349-2356]. CAUDA andcolleagues found that the human insula is functionally involved in twodistinct neural networks: i) the anterior pattern is related to theventralmost anterior insula, and is connected to the rostral anteriorcingulate cortex, the middle and inferior frontal cortex, and thetemporoparietal cortex; ii) the posterior pattern is associated with thedorsal posterior insula, and is connected to the dorsal-posteriorcingulate, sensorimotor, premotor, supplementary motor, temporal cortex,and to some occipital areas [CAUDA F, D'Agata F, Sacco K, Duca S,Geminiani G, Vercelli A. Functional connectivity of the insula in theresting brain. Neuroimage 55(1, 2011):8-23; CAUDA F, Vercelli A. Howmany clusters in the insular cortex? Cereb Cortex. 2012 Sep. 30. (Epubahead of print, pp. 1-2)]. TAYLOR and colleagues also report two suchresting networks [TAYLOR K S, Seminowicz D A, Davis K D. Two systems ofresting state connectivity between the insula and cingulate cortex. HumBrain Mapp 30(9, 2009):2731-2745]. DEEN and colleagues found three suchresting state networks [DEEN B, Pitskel N B, Pelphrey K A. Three systemsof insular functional connectivity identified with cluster analysis.Cereb Cortex 21(7, 2011):1498-1506]. The networks involving both theinsula and ACC are the ones that are preferably modulated according tothe present invention, because they are the ones most associated withpain and the awareness of unpleasant sensations [MALINEN S, VartiainenN, Hlushchuk Y, Koskinen M, Ramkumar P, Forss N, Kalso E, Hari R.Aberrant temporal and spatial brain activity during rest in patientswith chronic pain. Proc Natl Acad Sci USA. 2010 Apr. 6; 107(14,2010):6493-6497; Nick MEDFORD and Hugo D. Critchley. Conjoint activityof anterior insular and anterior cingulate cortex: awareness andresponse. Brain Struct Funct 214(5-6, 2010): 535-549].

The present invention modulates the activity of such resting statenetworks, via the locus ceruleus (or alternatively via another structurethat has widespread projections), by electrically stimulating a vagusnerve. Stimulation of a network via the locus ceruleus may activate ordeactivate a network, depending on the detailed configuration ofadrenergic receptor subtypes within the network and their roles inenhancing or depressing neural activity within the network, as well assubsequent network-to-network interactions. According to the invention,one key to preferential stimulation of a particular resting statenetwork, such as the DMN or those involving the insula and ACC, is touse a vagus nerve stimulation signal that entrains to the signature EEGpattern of that network (see below and MANTINI D, Perrucci M G, DelGratta C, Romani G L, Corbetta M. Electrophysiological signatures ofresting state networks in the human brain. Proc Natl Acad Sci USA104(32, 2007):13170-13175). By this EEG entrainment method, it may bepossible to preferentially attenuate or deactivate the insula/ACCnetworks in a patient, thereby reducing gastrointestinal pain or otherunpleasant sensations. Activation of another network such as the VAN orDMN may also produce the same effect, via network-to-networkinteractions. Although the locus ceruleus is presumed to project to allof the resting networks, it is thought to project most strongly to theventral attention network (VAN) [CORBETTA M, Patel G, Shulman G L. Thereorienting system of the human brain: from environment to theory ofmind. Neuron 58(3, 2008):306-24; MANTINI D, Corbetta M, Perrucci M G,Romani G L, Del Gratta C. Large-scale brain networks account forsustained and transient activity during target detection. Neuroimage44(1, 2009):265-274]. Thus, deactivation of a particular network mayalso be attempted by activating another resting state network, becausethe brain switches between them. Because the vagus nerve stimulationreduces pain by modulating resting state networks via the locusceruleus, the presently described mechanism differs from previouslyreported noradrenergic effects, which have nothing to do with restingstate networks [PERTOVAARA A. Noradrenergic pain modulation. ProgNeurobiol 80 (2006):53-83].

Description of the Magnetic and Electrode-Based NerveStimulating/Modulating Devices

Devices of the invention that are used to stimulate a vagus nerve willnow be described. Either a magnetic stimulation device or anelectrode-based device may be used for that purpose. FIG. 2A is aschematic diagram of Applicant's magnetic nerve stimulating/modulatingdevice 301 for delivering impulses of energy to nerves for the treatmentof medical conditions such as gastroparesis or functional dyspepsia. Asshown, device 301 may include an impulse generator 310; a power source320 coupled to the impulse generator 310; a control unit 330 incommunication with the impulse generator 310 and coupled to the powersource 320; and a magnetic stimulator coil 341 coupled via wires toimpulse generator coil 310. The stimulator coil 341 is toroidal inshape, due to its winding around a toroid of core material.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient, at the siteof stimulation on the skin, than stimulator devices that are currentlyknown in the art. Conversely, for a given amount of pain or discomforton the part of the patient (e.g., the threshold at which such discomfortor pain begins), the design achieves a greater depth of penetration ofthe stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 8), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 8), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmurlo, Przemyslaw Plonecki, JacekStarzyński, Stanislaw Wincenciak, Andrzej Rysz. Mathematical Modellingof Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A. ElectromagneticField, Health and Environment: Proceedings of EHE'07. Amsterdam, IOSPress, 2008]. Pulses may be monophasic, biphasic or polyphasic.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseprevailing conditions prevailing in this substance, whereby the user ofthe system can manually adjust the signal, or have it automaticallyadjusted by feedback, to provide an electrical stimulation signal ofwhatever type the user wishes, who can then observe the effect of thissignal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 100 Hz, more preferably around 25 Hz. The modulationsignal may have a pulse width selected to influence the therapeuticresult, such as about 1 microseconds to about 1000 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to 600 V/m, preferablyless than 100 V/m, and even more preferably less than 30 V/m. Thegradient of the electric field may be greater than 2 V/m/mm. Moregenerally, the stimulation device produces an electric field in thevicinity of the nerve that is sufficient to cause the nerve todepolarize and reach a threshold for action potential propagation, whichis approximately 8 V/m at 1000 Hz. The modulation signal may have a peakvoltage amplitude selected to influence the therapeutic result, such asabout 0.2 volts or greater, such as about 0.2 volts to about 40 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J. Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of τ, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period τ may be 200 microseconds; the numberof pulses per burst may be N=5; and the whole pattern of burst followedby silent inter-burst period may have a period of T=40000 microseconds,which is comparable to 25 Hz stimulation (a much smaller value of T isshown in FIG. 2E to make the bursts discernable). When these exemplaryvalues are used for T and τ, the waveform contains significant Fouriercomponents at higher frequencies ( 1/200 microseconds=5000/sec), ascompared with those contained in transcutaneous nerve stimulationwaveforms, as currently practiced.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters τ, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med 10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to DE RIDDER, entitled Stimulation design for neuromodulation;application US20110184486 to DE RIDDER, entitled Combination of tonicand burst stimulations to treat neurological disorders]. By way ofexample, the electric field shown in FIGS. 2D and 2E may have an E_(max)value of 17 V/m, which is sufficient to stimulate the nerve but issignificantly lower than the threshold needed to stimulate surroundingmuscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011]. Those methodsinvolve high-frequency modulation in the range of from about 1.5 KHz toabout 50 KHz, which is applied to the patient's spinal cord region.However, such methods are different from the present invention because,for example, they is invasive; they do not involve a bursting waveform,as in the present invention; they necessarily involve A-delta and Cnerve fibers and the pain that those fibers produce, whereas the presentinvention does not; they may involve a conduction block applied at thedorsal root level, whereas the present invention may stimulate actionpotentials without blocking of such action potentials; and/or theyinvolve an increased ability of high frequency modulation to penetratethrough the cerebral spinal fluid, which is not relevant to the presentinvention. In fact, a likely explanation for the reduced back pain thatis produced by their use of frequencies from 10 to 50 KHz is that theapplied electrical stimulus at those frequencies causes permanent damageto the pain-causing nerves, whereas the present invention involves onlyreversible effects [LEE R C, Zhang D, Hannig J. Biophysical injurymechanisms in electrical shock trauma. Annu Rev Biomed Eng 2(2000):477-509].

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The waveform disclosed in FIG. 2 containssignificant Fourier components at high frequencies (e.g., 1/200microseconds=5000/sec), even if the waveform also has components atlower frequencies (e.g., 25/sec). Transcutaneously, A-beta, A-delta, andC fibers are typically excited at 2000 Hz, 250 Hz, and 5 Hz,respectively, i.e., the 2000 Hz stimulus is described as being specificfor measuring the response of A-beta fibers, the 250 Hz for A-deltafibers, and the 5 Hz for type C fibers [George D. BAQUIS et al.TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTION THRESHOLD (CPT).Muscle Nerve 22(Supplement 8, 1999): S247-S259]. Therefore, the highfrequency component of the noninvasive stimulation waveform willpreferentially stimulate the A-alpha and A-beta fibers, and the C fiberswill be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol 104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to 100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 to100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS M S, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110 (2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282 (1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

To summarize the foregoing discussion, the delivery, in a patientsuffering from gastroparesis or functional dyspepsia, of an impulse ofenergy sufficient to stimulate and/or modulate transmission of signalsof vagus nerve fibers will result in improved gastric mobility and morenormal interoception. The most likely mechanisms do not involve thestimulation of C fibers; and the stimulation of afferent nerve fibersactivates neural pathways causing the release of norepinephrine, and/orserotonin and/or GABA.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 8). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Embodiments of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e, z and ρ are used to specify location of the field, notx, y, and z). This is a significant limitation, and it results in adeficiency that was noted in FIG. 6 of their publication: “at largedepths of stimulation, the threshold current [in the device's coil] forlong axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima.

In the dissertation cited above, Carbunaru—FAIERSTEIN made no attempt touse conducting material other than agar in a KCl solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG.2A as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.This allows for minimal heating of the coil(s) and deeper tissuestimulation. However, application of the conducting medium to thesurface of the patient is difficult to perform in practice because thetissue contours (head, arms, legs, neck, etc.) are not planar. To solvethis problem, in the preferred embodiment of the present invention, thetoroidal coil is embedded in a structure which is filled with aconducting medium having approximately the same conductivity as muscletissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCl solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the magnetic stimulation device is shown inFIG. 3. FIGS. 3A and 3B respectively provide top and bottom views of theouter surface of the toroidal magnetic stimulator 30. FIGS. 3C and 3Drespectively provide top and bottom views of the toroidal magneticstimulator 30, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPoison]. Conventional magnetic nerve stimulators use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator 310, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology 85 (1992): 253-264;Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey. The effects of pulseconfiguration on magnetic stimulation. Journal of ClinicalNeurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 3.

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.Therefore, with the present invention, it is possible to generatewaveforms shown in FIG. 2 with relatively simple, low-power circuitsthat are powered by batteries. The circuits may be enclosed within a box38 as shown in FIG. 3E, or the circuits may be attached to thestimulator itself (FIG. 3A-3D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiments of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. U.S. Pat. No. 7,340,299, entitledMethods of indirectly stimulating the vagus nerve to achieve controlledasystole, to John D. PUSKAS, discloses the stimulation of the vagusnerve using electrodes placed on the neck of the patient, but thatpatent is unrelated to the treatment of gastroparesis or functionaldyspepsia. Non-invasive electrical stimulation of the vagus nerve hasalso been described in Japanese patent application JP2009233024A with afiling date of Mar. 26, 2008, entitled Vagus Nerve Stimulation System,to Fukui YOSHIHOTO, in which a body surface electrode is applied to theneck to stimulate the vagus nerve electrically. However, thatapplication pertains to the control of heart rate and is unrelated tothe treatment of gastroparesis or functional dyspepsia.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimulator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. However, none of thedisclosures in these patents or patent applications for electricalstimulation of the vagus nerve at the ear are used to treatgastroparesis or functional dyspepsia.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.4A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 4B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 4B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or more thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 4Cand 4D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 4D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) is filled with conducting material (350 in FIG. 2B),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 4, or it may be tubularor conical or have some other inner surface geometry that will affectthe Neumann boundary conditions that determine the electric fieldstrength.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 4C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 4C and 4D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 4D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range 0.5 to1.5 microns) having a dielectric constant of about 3. Because one sideof Mylar is slick, and the other side is microscopically rough, thepresent invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with a dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm) because the dielectricconstant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2). In addition, the capacitive electrode allows for the use of aninterface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113 (1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25 (1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25 (1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 2B) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71 (1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 4 and 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 4and 5 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21 (1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71 (1999): 4944-4950].In fact, patients found the design shown in FIGS. 4 and 5 to be lesspainful in a direct comparison with a commercially availablegrid-pattern electrode [UltraStim grid-pattern electrode, AxelggardManufacturing Company, 520 Industrial Way, Fallbrook Calif., 2011]. Theembodiment of the electrode that uses capacitive coupling isparticularly suited to the generation of uniform stimulation currents[Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of currentdensity under stimulating electrodes. Critical Reviews in BiomedicalEngineering 17(1990, 6): 585-619].

The electrode-based stimulator designs shown in FIGS. 4 and 5 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electrode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No.4,182,346, and U.S. Pat. No. 3,973,557, entitled Electrode, to Allisonet al; U.S. Pat. No. 4,215,696, entitled Biomedical electrode withpressurized skin contact, to Bremer et al; and U.S. Pat. No. 4,166,457,entitled Fluid self-sealing bioelectrode, to Jacobsen et al.] Thestimulator designs shown in FIGS. 4 and 5 are also self-contained units,housing the electrodes, signal electronics, and power supply. Portablestimulators are also known in the art, for example, U.S. Pat. No.7,171,266, entitled Electro-acupuncture device with stimulationelectrode assembly, to Gruzdowich. One of the novelties of the designsshown in FIGS. 4 and 5 is that the stimulator, along with acorrespondingly suitable stimulation waveform, shapes the electricfield, producing a selective physiological response by stimulating thatnerve, but avoiding substantial stimulation of nerves and tissue otherthan the target nerve, particularly avoiding the stimulation of nervesthat produce pain. The shaping of the electric field is described interms of the corresponding field equations in commonly assignedapplication US20110230938 (application Ser. No. 13/075,746) entitledDevices and methods for non-invasive electrical stimulation and theiruse for vagal nerve stimulation on the neck of a patient, to SIMON etal., which is hereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 5C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 5D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3, 4 and 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 5 is shown to be applied to thetarget location on the patient's neck as described above. For reference,locations of the following vertebrae are also shown: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77.

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. Stimulation may be performed on the left orright vagus nerve or on both of them simulataneously or alternately. Theposition and angular orientation of the device are adjusted about thatlocation until the patient perceives stimulation when current is passedthrough the stimulator electrodes. The applied current is increasedgradually, first to a level wherein the patient feels sensation from thestimulation. The power is then increased, but is set to a level that isless than one at which the patient first indicates any discomfort.Straps, harnesses, or frames are used to maintain the stimulator inposition (not shown in FIG. 6). The stimulator signal may have afrequency and other parameters that are selected to produce atherapeutic result in the patient. Stimulation parameters for eachpatient are adjusted on an individualized basis. Ordinarily, theamplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period τ may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of 1 to 1000 microseconds (i.e., about 1 to 10 KHz),preferably 200 microseconds (about 5 KHz). A burst followed by a silentinter-burst interval repeats at 1 to 5000 bursts per second (bps),preferably at 5-50 bps, and even more preferably 10-25 bps stimulation(10-25 Hz). The preferred shape of each pulse is a full sinusoidal wave,although triangular or other shapes may be used as well. For somepatients, the stimulation may be performed for 30 minutes, and thetreatment is performed several times a week for 12 weeks or longer,because the disease is a chronic situation that requires a substantialperiod to reverse the pathophysiology. For patients experiencingintermittent symptoms, the treatment may be performed only when thepatient is symptomatic. However, it is understood that parameters of thestimulation protocol may be varied in response to heterogeneity in thepathophysiology of patients. Different stimulation parameters may alsobe selected as the course of the patient's disease changes.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a additional sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect.

For example, the hypothalamus is well known to be responsive to thepresence of bright light, so exposing the patient to bright light thatis fluctuating with the same stimulation frequency as the vagus nerve(or a multiple of that frequency) may be performed in an attempt toenhance the role of the hypothalamus in producing the desiredtherapeutic effect. Such paired stimulation does not necessarily relyupon neuronal plasticity and is in that sense different from otherreports of paired stimulation [Navzer D. ENGINEER, Jonathan R. Riley,Jonathan D. Seale, Will A. Vrana, Jai A. Shetake, Sindhu P. Sudanagunta,Michael S. Borland and Michael P. Kilgard. Reversing pathological neuralactivity using targeted plasticity. Nature 470(7332, 2011):101-104;PORTER B A, Khodaparast N, Fayyaz T, Cheung R J, Ahmed S S, Vrana W A,Rennaker R L 2nd, Kilgard M P. Repeatedly pairing vagus nervestimulation with a movement reorganizes primary motor cortex. CerebCortex 22(10, 2012):2365-2374].

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006)179-84]. Thus, by performing the imaging with different setsof stimulation parameters, a database may be constructed, such that theinverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

Stimulation waveforms may also be constructed by superimposing or mixingthe burst waveform shown in FIG. 2, in which each component of themixture may have a different period T, effectively mixing differentburst-per-second waveforms. The relative amplitude of each component ofthe mixture may be chosen to have a weight according to correlations indifferent bands in an EEG for a particular resting state network. Thus,MANTINI et al performed simultaneous fMRI and EEG measurements and foundthat each resting state network has a particular EEG signature [see FIG.3 in: MANTINI D, Perrucci M G, Del Gratta C, Romani G L, Corbetta M.Electrophysiological signatures of resting state networks in the humanbrain. Proc Natl Acad Sci USA 104(32, 2007)13170-13175]. They reportedrelative correlations in each of the following bands, for each restingstate network that was measured: delta (1-4 Hz), theta (4-8 Hz), alpha(8-13 Hz), beta (13-30 Hz), and gamma (30-50 Hz) rhythms. Forrecently-identified resting state networks, measurement of thecorresponding signature EEG networks will have to be performed.

According to the present embodiment of the invention, multiple signalsshown in FIG. 2 are constructed, with periods T that correspond to alocation near the midpoint of each of the EEG bands (e.g., using theMINATI data, T equals approximately 0.4 sec, 0.1667 sec, 0.095 sec,0.0465 sec, and 0.025 sec, respectively). A more comprehensive mixturecould also be made by mixing more than one signal for each band. Thesesignals are then mixed, with relative amplitudes corresponding to theweights measured for any particular resting state network, and themixture is used to stimulate the vagus nerve of the patient. Phasesbetween the mixed signals are adjusted to optimize the fMRI signal forthe resting state network that is being stimulated. Stimulation of anetwork may activate or deactivate a network, depending on the detailedconfiguration of adrenergic receptors within the network and their rolesin enhancing or depressing neural activity within the network, as wellas subsequent network-to-network interactions. It is understood thatvariations of this method may be used when different combined fMRI-EEGprocedures are employed and where the same resting state may havedifferent EEG signatures, depending on the circumstances [WU C W, Gu H,Lu H, Stein E A, Chen J H, Yang Y. Frequency specificity of functionalconnectivity in brain networks. Neuroimage 42(3, 2008):1047-1055; LAUFSH. Endogenous brain oscillations and related networks detected bysurface EEG-combined fMRI. Hum Brain Mapp 29(7, 2008):762-769; MUSSO F,Brinkmeyer J, Mobascher A, Warbrick T, Winterer G. Spontaneous brainactivity and EEG microstates. A novel EEG/fMRI analysis approach toexplore resting-state networks. Neuroimage 52(4, 2010):1149-1161;ESPOSITO F, Aragri A, Piccoli T, Tedeschi G, Goebel R, Di Salle F.Distributed analysis of simultaneous EEG-fMRI time-series: modeling andinterpretation issues. Magn Reson Imaging 27(8, 2009):1120-1130; FREYERF, Becker R, Anami K, Curio G, Villringer A, Ritter P.Ultrahigh-frequency EEG during fMRI: pushing the limits ofimaging-artifact correction. Neuroimage 48(1, 2009):94-108].

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted. Alternatively, the selection ofparameter values may involve tuning as understood in control theory, andas described below. It is understood that parameters may also be variedrandomly in order to simulate normal physiological variability, therebypossibly inducing a beneficial response in the patient [Buchman T G.Nonlinear dynamics, complex systems, and the pathobiology of criticalillness. Curr Opin Crit Care 10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve; to avoid potentially dangerous situationssuch as excessive heart rate; and to maintain measured EEG bands (e.g.,delta, theta, alpha, beta) within predetermined ranges, in attempt topreferentially activate particular resting state networks. Thus, withthese methods, the parameters of the vagus nerve stimulation may bechanged automatically, depending on physiological measurements that aremade, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

The effects of vagus nerve stimulation on surface EEG waveforms may bedifficult to detect [Michael BEWERNITZ, Georges Ghacibeh, Onur Seref,Panos M. Pardalos, Chang-Chia Liu, and Basim Uthman. Quantification ofthe impact of vagus nerve stimulation parameters onelectroencephalographic measures. AIP Conf. Proc. DATA MINING, SYSTEMSANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007, Volume 953, pp.206-219], but they may exist nevertheless [KOO B. EEG changes with vagusnerve stimulation. J Clin Neurophysiol. 18(5, 2001):434-41; KUBA R,Guzaninová M, Brázdil M, Novák Z, Chrastina J, Rektor I. Effect of vagalnerve stimulation on interictal epileptiform discharges: a scalp EEGstudy. Epilepsia. 43(10, 2002):1181-8; RIZZO P, Beelke M, De Carli F,Canovaro P, Nobili L, Robert A, Formaro P, Tanganelli P, Regesta G,Ferrillo F. Modifications of sleep EEG induced by chronic vagus nervestimulation in patients affected by refractory epilepsy. ClinNeurophysiol. 115(3, 2004):658-64].

When stimulating the vagus nerve, motion variability is most oftenattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 7).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods. As shown there, the patient, or the relevantphysiological component of the patient, is considered to be the “System”that is to be controlled. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound. If the “System” is defined to be only aparticular physiological component of the patient, the “Environment” mayalso be considered to include physiological systems of the patient thatare not included in the “System”. Thus, if some physiological componentcan influence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2. Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington M A. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For monitoring myoelectric activity of the patient's stomach, thesensors may comprise those used for cutaneous electrogastrograms [ZhiyueLIN. Noninvasive diagnosis of delayed gastric emptying from cutaneouselectrogastrograms using neural networks. Proceedings of theInternational Conference on Neural Networks (1, 1997):67-70 (HoustonTex., 9 Jun. 1997-12 Jun. 1997); CHEN J D, Zou X, Lin X, Ouyang S, LiangJ. Detection of gastric slow wave propagation from the cutaneouselectrogastrogram. Am J Physiol 277(2 Pt 1, 1999):G424-G430; LAWLOR P M,McCullough J A, Byrne P J, Reynolds J V. Electrogastrography: anon-invasive measurement of gastric function. Ir J Med Sci 170(2,2001):126-131].

Noninvasive methods also exist for the measurement of gastric emptying,some of which would have to be adapted for use in ambulatory monitoring[G R McCLELLAND and J A Sutton. Epigastric impedance: a non-invasivemethod for the assessment of gastric emptying and motility. Gut 26(6,1985): 607-614; Masaka SANAKI and Koji Nakada. Stable isotope breathtests for assessing gastric emptying: a comprehensive review. J SmoothMuscle Res 46 (2010):267-280; GREMLICH H U, Martínez V, Kneuer R, KinzyW, Weber E, Pfannkuche H J, Rudin M. Noninvasive assessment of gastricemptying by near-infrared fluorescence reflectance imaging in mice:pharmacological validation with tegaserod, cisapride, and clonidine. MolImaging 3(4, 2004):303-311].

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst 34(2010)195-212]. In the present application, the features would includeEEG bands (e.g., delta, theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. After digitizing such signals, the phase ofrespiration may be determined using software such as “puka”, which ispart of PhysioToolkit, a large published library of open source softwareand user manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov P Ch, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a NewResearch Resource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to thegastrointestinal problem that is addressed here, but it does considerstimulation during particular phases of the respiratory cycle, for thefollowing reason. Because the vagus nerve is near the phrenic nerve,Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

Patent application publication US2009/0177252, entitled Synchronizationof vagus nerve stimulation with the cardiac cycle of a patient, toArthur D. Craig, discloses a method of treating a medical condition inwhich the vagus nerve is stimulated during a portion of the cardiaccycle and the respiratory cycle. That disclosure pertains to thetreatment of a generic medical condition, so it is not specificallydirected to the treatment of gastrointestinal problems.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, so as toachieve and maintain the heart rate within safe or desired limits. Inthat case, the parameters of the stimulation are individually raised orlowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treat gastrointestinalproblems, embodiments of the invention described above may be used toachieve and maintain the heart rate and blood pressure within desiredranges.

Let the measured output variables of the system in FIG. 8 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 8 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 8.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed to perform neck movements,breathe deeply so as to contract the sternocleidomastoid muscle, andgenerally simulate possible motion that may accompany prolongedstimulation with the stimulator. This would include possible slippage ormovement of the stimulator relative to an initial position on thepatient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurlo,Przemyslaw Plonecki, Jacek Starzyński, Stanislaw Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(j)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form: u(t)=K_(p)e(t)+K_(i)∫₀^(t)e(τ)dτ+K_(d)de/dt where the parameters for the controller are theproportional gain (K_(p)), the integral gain (K_(i)) and the derivativegain (K_(d)). This type of controller, which forms a controlling inputsignal with feedback using the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [L I, Y., Ang, K. H. and Chong, G. C. Y. Patents, softwareand hardware for PID control: an overview and analysis of the currentart. IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl JohanÅström & Richard M. Murray. Feedback Systems: An Introduction forScientists and Engineers. Princeton N.J.: Princeton University Press,2008; Finn HAUGEN. Tuning of PID controllers (Chapter 10) In: BasicDynamics and Control. 2009. ISBN 978-82-91748-13-9. TechTeach,Enggravhøgda 45, N-3711 Skien, Norway. http://techteach.no., pp.129-155; Dingyu XUE, YangQuan Chen, Derek P. Atherton. PID controllerdesign (Chapter 6), In: Linear Feedback Control: Analysis and Designwith MATLAB. Society for Industrial and Applied Mathematics (SIAM).3600Market Street, 6th Floor, Philadelphia, Pa. (2007), pp. 183-235; JanJANTZEN, Tuning Of Fuzzy PID Controllers, Technical University ofDenmark, report 98-H 871, Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. To use such a controller, forexample, in an attempt to maintain the EEG gamma band at a particularlevel relative to the alpha band, one could set the integral andderivative gains to zero, increase the proportional gain (amplitude ofthe stimulation) until the relative gamma band level starts tooscillate, and then measure the period of oscillation. The PID wouldthen be set to its tuned parameter values.

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

The controller shown in FIG. 8 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 8 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

Performance of system control can be improved by combining the feedbackclosed-loop control of a PID controller with feed-forward control,wherein knowledge about the system's future behavior can be fed forwardand combined with the PID output to improve the overall systemperformance. For example, if the sensed environmental input in FIG. 8 issuch the environmental input to the system will have a deleteriouseffect on the system after a delay, the controller may use thisinformation to provide anticipatory control input to the system, so asto avert or mitigate the deleterious effects that would have been sensedonly after-the-fact with a feedback-only controller.

Many patients with gastroparesis and/or functional dyspepsia exhibitsymptoms intermittently, but recurrently, in which the patient isasymptomatic for an extended period of time, but then symptoms reappearupon ingestion of a meal. It would be useful to predict when thesymptoms will be imminent, so that the patient may perform vagus nervestimulation as a prophylactic and adjust meal content and portions. Amathematical model of the system is needed in order to perform thepredictions of system behavior, e.g., make predictions concerning theonset of symptoms of gastroparesis (and/or functional dyspepsia). Modelsthat are completely based upon physical first principles (white-box) arerare, especially in the case of physiological systems. Instead, mostmodels that make use of prior structural and mechanistic understandingof the system are so-called grey-box models. If the mechanisms of thesystems are not sufficiently understood in order to construct a white orgrey box model, a black-box model may be used instead. Such black boxmodels comprise autoregressive models [Tim BOLLERSLEV. Generalizedautoregressive condiditional heteroskedasticity. Journal of Econometrics31 (1986):307-327], or those that make use of principal components[James H. STOCK, Mark W. Watson. Forecasting with Many Predictors, In:Handbook of Economic Forecasting. Volume 1, G. Elliott, C. W. J. Grangerand A. Timmermann, eds (2006) Amsterdam: Elsevier B. V, pp 515-554],Kalman filters [Eric A. WAN and Rudolph van der Merwe. The unscentedKalman filter for nonlinear estimation, In: Proceedings of Symposium2000 on Adaptive Systems for Signal Processing, Communication andControl (AS-SPCC), IEEE, Lake Louise, Alberta, Canada, October, 2000, pp153-158], wavelet transforms [O. RENAUD, J.-L. Stark, F. Murtagh.Wavelet-based forecasting of short and long memory time series. SignalProcessing 48 (1996):51-65], hidden Markov models [Sam ROWEIS and ZoubinGhahramani. A Unifying Review of Linear Gaussian Models. NeuralComputation 11(2, 1999): 305-345], or artificial neural networks[Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecasting withartificial neural networks: the state of the art. International Journalof Forecasting 14 (1998): 35-62].

For the present invention, if a black-box model must be used, thepreferred model will be one that makes use of support vector machines. Asupport vector machine (SVM) is an algorithmic approach to the problemof classification within the larger context of supervised learning. Anumber of classification problems whose solutions in the past have beensolved by multi-layer back-propagation neural networks, or morecomplicated methods, have been found to be more easily solvable by SVMs[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2 (1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, S A; Vetterling, W T; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes:The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

In this example, a training set of physiological data will have beenacquired that includes whether or not the patient is experiencingsymptoms of gastroparesis (and/or functional dyspepsia). Thus, theclassification of the patient's state is whether or not the symptoms arepresent, and the data used to make the classification consist of theacquired physiological data: electrogastrogram, EEG and its derivedfeatures; respiration (abdominal and thoracic plethysmography), carbondioxide (capnometry with nasual cannula), heart rate (electrocardiogramleads), skin impedance (electrodermal leads), vocalization(microphones), light (light sensor), motion (accelerometer), externaland finger temperature (thermometers), etc., as well as parameters ofthe stimulator device (if it is currently being used on a patientexperiencing symptoms), evaluated at Δ time units prior to the time atwhich binary “symptoms present” (yes/no) data are acquired, as indicatedby the patient or a caregiver. Thus, for a patient who is experiencingsymptoms, the SVM is trained to forecast the termination of symptoms, Δtime units into the future, and the training set includes thetime-course of features extracted from the above-mentioned physiologicalsignals. For a patient who is not experiencing symptoms, the SVM istrained to forecast the imminence of symptoms, Δ time units into thefuture, and the training set includes the above-mentioned physiologicalsignals. After training the SVM, it is implemented as part of thecontroller. For patients who are not experiencing symptoms, thecontroller may sound an alarm and advise the use of vagal nervestimulation (or other intervention), whenever there is a forecast ofimminent symptoms.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A method of treating or preventing gastroparesisand/or functional dyspepsia in a patient, comprising: positioning adevice adjacent to a skin surface of the patient; generating one or moreshaped electrical impulses with said device; and transmitting theelectrical impulses to selected nerve fibers in the patient, wherein theelectrical impulses are sufficient to modify gastroparesis and/orfunctional dyspepsia within the patient.
 2. The method of claim 1wherein the transmitting step comprises transmitting the electricalimpulses from one or more electrodes through a conducting medium withinthe device.
 3. The method of claim 1 wherein the electrical impulses aretransmitted transcutaneously through an outer skin surface of thepatient to generate an electrical impulse at or near the selected nervefibers.
 4. The method of claim 3 further comprising generating anelectrical field at or near the device and shaping the electrical fieldsuch that the electrical field is sufficient to modulate a nerve fiberat the target region; and wherein the electric field is not sufficientto substantially modulate a nerve or muscle between the outer skinsurface and the target region.
 5. The method of claim 4 wherein theelectric field at the nerve fiber at the target region is between about10 to 600 V/m.
 6. The method of claim 5 wherein the electric field isless than 100 V/m.
 7. The method of claim 4 wherein the nerve fiber atthe target region is at least approximately 0.5-2 cm below an outerskin-surface of the patient.
 8. The method of claim 1 wherein theselected nerve fibers are associated with a vagus nerve of the patient.9. The method of claim 1 wherein the electrical impulses comprise burstsof pulses with a frequency of between about 1 to 100 bursts per second.10. The method of claim 9 wherein each bursts contains between 1 and 20pulses.
 11. The method of claim 9 wherein the pulses are full sinusoidalwaves.
 12. The method of claim 9 wherein each pulse is about 100 to 1000microseconds in duration.
 13. The method of claim 12 wherein theduration of a pulse within a burst is about 200 microseconds, whereinthe number of pulses per burst is between 4 and 6, and wherein thenumber of bursts per second is between 20 and
 30. 14. The method ofclaim 1 wherein the selected nerve fibers control or modulate therelease of a trophic factor for an interstitial cell of Cajal.
 15. Themethod of claim 1 wherein the selected nerve fibers are afferent nervefibers.
 16. The method of claim 1 the electrical impulses generate anelectric field at the vagus nerve above a threshold for generatingaction potentials within A and B fibers of the vagus nerve and below athreshold for generating action potentials within C fibers of the vagusnerve.
 17. The method of claim 1 wherein the electrical impulsesgenerate an electric field at the vagus nerve above a threshold forgenerating action potentials within fibers of the vagus nerveresponsible for activating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 18. The method of claim17 wherein the inhibitory neurotransmitters comprise norepinephrine. 19.The method of claim 17 wherein neural activity within an area postremais inhibited.
 20. The method of claim 18 wherein the norepinephrine isreleased into a resting state neural network of the patient.
 21. Themethod of claim 20 wherein the resting state network comprises a part ofan anterior insula and/or an anterior cingulate cortex.
 22. A device fortreating or preventing gastroparesis or functional dyspepsia in apatient comprising: a housing having an electrically permeable contactsurface for contacting an outer skin surface of the patient; an energysource within the housing configured to generate an electric fieldsufficient to transmit a shaped electric current through the outer skinsurface of the patient to a nerve at a target region within the patient;wherein the electric current is sufficient to treat gastroparesis orfunctional dyspepsia in the patient.
 23. The device of claim 22 whereinthe energy source comprises a signal generator and one or moreelectrodes coupled to the signal generator within the housing.
 24. Thedevice of claim 23 further comprising a conducting medium within thehousing between the electrodes and the electrically permeable contactsurface.
 25. The device of claim 22 wherein the energy source comprisesa battery.
 26. The device of claim 22 wherein the electric fieldcomprises bursts of pulses with a frequency of about 1 to about 100bursts per second.
 27. The device of claim 26 wherein the electric fieldcomprises bursts of between 1 and 50 pulses per burst, with each pulsebeing about 50 to 1000 microseconds in duration.
 28. The device of claim22 wherein the electric current is sufficient to stimulate a vagus nerveof the patient.
 29. The device of claim 22 wherein the housing is ahandheld device configured for contacting a surface of the skin of apatient.
 30. The device of claim 22 wherein the electrical impulsesgenerate an electric field at the vagus nerve above a threshold forgenerating action potentials within A and B fibers of the vagus nerveand below a threshold for generating action potentials within C fibersof the vagus nerve.
 31. The device of claim 22 wherein the electricalimpulses generate an electric field at the vagus nerve above a thresholdfor generating action potentials within fibers of the vagus nerveresponsible for activating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 32. The device of claim31 wherein the inhibitory neurotransmitters comprise norepinephrine. 33.The device of claim 32 wherein neural activity within an area postremais inhibited.
 34. The device of claim 32 wherein the norepinephrine isreleased into a resting state neural network of the patient.
 35. Thedevice of claim 34 wherein the resting state network comprises a part ofan anterior insula and/or an anterior cingulate cortex.